This page lists the previous five years of Research Seed Award winners. For information about earlier funded projects, please email firstname.lastname@example.org .
Biological and Life Sciences
Inhibiting T. brucei polo-like kinase as a novel approach for treating sleeping sickness
Trypansoma brucei is the causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness, and nagana in cattle. These diseases cause extraordinary suffering in Sub-Saharan Africa, leading to many deaths and profound economic hardship. The few drugs available for treating HAT are extremely toxic and resistance to many of them has appeared in the field. Identifying cellular processes that can be targeted for drug discovery, ideally ones that are both unique to the parasite (to limit any detrimental effect on the mammalian host) and critical for its survival (so that its inhibition will kill or render the parasite incapable of dividing) is essential to spur the design of new therapeutics for treating HAT. We have recently demonstrated that the polo-like kinase homolog in T. brucei (TbPLK), and its substrates TbCentrin2 and TOEFAZ1 are essential for T. brucei cell division. Here we will use multiple approaches -- biochemistry, biophysics, cell biology and medicinal chemistry in order to elucidate the molecular basis of the TbPLK-substrate interaction and to identify novel inhibitors that block the interaction of TbPLK with its substrates.
PI: Christopher de Graffenried, Assistant Professor, Molecular Microbiology and Immunology
Co-PI: Rebecca Page, Professor, Molecular Biology, Cell Biology and Biochemistry; Michael Pollastri, Department of Chemistry and Chemical Biology, Northeastern University
Visualizing the dynamic architecture of germ granules
How do eukaryotic cells dynamically and spatially regulate gene expression during embryonic development, neural function, and cellular stress? Recently, breakthrough studies have identified micron sized granule structures composed of protein and mRNA as liquid-like physiological RNA processing and localization centers that are disrupted in disease. Unlike much of the complex machinery performing essential cell functions, there is poor understanding of the mechanistic function of the assemblies because no structural information is available on either the components or their interactions within these granules. The assembled team will directly address this critical gap in knowledge by applying complementary and collaborative structure/function experiments on the disordered protein:protein interaction domains that invariably are found in granule nucleating proteins. The proposed project will 1) test the functional significance of these “sticky” regions on granule localization and assembly within Xenopus laevis oocytes and 2) determine the atomic structure and intermolecular contacts of these regions both in vitro and in vivo. This project combines the strengths and recent successes of the laboratories uniquely suited to the goals. The project will use in vivo fluorescence imaging and in cell NMR approaches to map the specific contributions of structurally disordered domains to interactions that undergird granule assembly. The long-term goals of these studies will be to determine the molecular mechanisms of granule formation and RNA transport.
PI: Nicolas Fawzi, Assistant Professor, Molecular Pharmacology, Physiology and Biotechnology
Co-PI: Kimberly Mowry, Professor and Chair, Molecular Biology, Cell Biology and Biochemistry
Probing nutrient cycling in re-growing tropical forests to gain insights into local, regional and global biogeochemical cycles
Over 50% of tropical rainforests are re-growing from recent abandonment of grazing or agricultural land. These land uses typically deplete soil fertility, particularly nitrogen availability, which can constrain forest regrowth. In the coming decades, secondary tropical forests will play a critical role in absorbing carbon dioxide from the atmosphere, providing habitat for myriad species, and food, fuel and fiber to millions of people. We seek funds to gather preliminary data on nitrogen cycling in perhaps the least studied - and most threatened - tropical forest biome on Earth: The Atlantic Forest of Brazil. This ancient forest, as diverse as the Amazon, once stretched over 1,500 km along the east coast of Brazil, but is now 85% deforested. Its remnants house some of the highest levels of biodiversity on earth and there is increasing interest in its restoration. In order to understand how, where, and why secondary forests regrow (both planted and natural regeneration), we propose a series of experiments in a sequence of secondary forest sites that differ in age. Our data will add substantially to our understanding of secondary tropical forest nutrient cycling, and will inform restoration by focusing on a key group of organisms that are critical to the restoration of these forests - nitrogen-fixing trees. This work will provide training for postdoctoral research scholar, produce data that will be used in at least one grant proposal submission (to the National Science Foundation), and provide enough data for two high impact peer-reviewed publications.
PI: Stephen Porder, Associate Professor, Ecology and Evolutionary Biology and Environment and Society
Co-PI: Meredith Hastings, Associate Professor, Environment and Society and Earth, Environmental and Planetary Sciences
Drosophila as a translational model to study renal fibrosis
Renal fibrosis is a feature of chronic kidney disease that contributes to proteinuria, hypertension and renal failure. Many factors precipitate renal fibrosis including infection, osmotic stress, kidney injury and hormones. In particular, the steroid hormone aldosterone plays a role in fibrosis, but the mechanisms by which it does so, and how initial kidney injury induces its pathogenic effects are open, pressing problems. Accordingly, we anticipate a forthcoming NIH initiative to request animal (non-mouse) models of renal fibrosis. Toward this end we are working with the Drosophila Malpighian (renal) tubule system and have found that steroid hormones, including mammalian aldosterone and insect ecdysone, induce excess extracellular deposition of collagen IV (pericardin) at renal tubules and podocytes. Consistent with the pathology of renal fibrosis, mammalian aldosterone given to Drosophila reduces renal and cardiac function. To prepare for the anticipated NIH Request for Applications of renal disease models we aim to 1) Determine if aldosterone/ecdysone uses G-protein coupled receptor dopEcR (human GPER) signaling to regulate pericardin (collagen IV), 2) Establish proof of concept for drugs to moderate fly-modeled renal fibrosis, 3) Establish that fly kidney injury initiates renal fibrosis via aldosterone/ecdysone. Together these studies would position our Drosophila model and research team at Brown University to study underlying mechanisms of renal fibrosis, establish its potential as a tool to discover kidney disease therapy, and compete for a targeted funding opportunity.
Developing a novel, high-throughput platform to study enzyme promiscuity
Enzymes are proteins that catalyze specific biochemical reactions. It is increasingly appreciated that in addition to their primary functions, many if not most enzymes have the capacity to also catalyze secondary reactions. However, the evolutionary role of such promiscuous enzymatic activities is poorly understood. We have developed a new research program to study the evolutionary implications of enzyme promiscuity, using the KpnI restriction enzyme as our model system. This enzyme cleaves DNA at a specific DNA recognition sequence, and defends the bacterium K. pneumonia against bacteria-specific viral pathogens called bacteriophage. OVPR Seed funding will support the development of a high-throughput experimental platform to quantify promiscuity in this system. Our approach subjects a large panel of KpnI variants to selection for their primary and promiscuous activities, and uses deep sequencing to quantify the resulting change in frequency of each variant. The project will generate a comprehensive map between all single amino acid mutations in KpnI and their effects on both primary and promiscuous KpnI activities. The results will constitute critical preliminary data for an R01 proposal investigating selection on promiscuity and its role in evolution, to be submitted to NIGMS in collaboration between labs in the EEB and MMI departments. The experimental platform developed in this proposal will be generalizable to large-scale investigation of mutational consequences in other enzymes, and will thus produce critical experimental and computational expertise to conduct such experiments at Brown.
Retail Environmental Change to Encourage Healthy Eating among Southeast Asian (SEA) Families: Leveraging Multi-Sector Partnerships with Asian Markets, Community Organizations and SEA Families
Overweight and obesity are poorly understood among Asian children. The limited available evidence suggests that Southeast Asian (SEA) children (specifically Hmong, Cambodian and Laotian) experience higher rates of obesity and related comorbidities than other Asian subgroups and whites, that disparities begin in early childhood, and that SEA are more similar to Latinos and African Americans with respect to overweight/obesity rates and obesity-related comorbidities. These data indicate that intervention during childhood and early adolescence (7-12 years) is warranted. Our multidisciplinary team that includes investigators and local community organizations is uniquely positioned to develop such an intervention to address the nutrition and physical activity needs of SEA families. Our overall is to address the current gaps in obesity prevention research by: 1) Conducting formative research with food retailers, SEA parents, grandparents, and children to inform development of a multi-level healthy eating intervention that will combine a retail healthy eating marketing campaign and financial incentives with a family based nutrition education intervention and; 2) Implementing the open pilot study to evaluate feasibility, acceptability and the preliminary efficacy of the intervention and to inform the design and implementation of a future RCT. We will use these data in an intervention mapping approach to plan a future NIH R01 submission. This research will position Brown at the forefront of obesity research with unique expertise in multi-level obesity prevention with SEA, a high priority, but extremely underserved group. This national reputation will be cemented further as Asians are the fasting growing racial group in the US.
PI: Akilah Dulin Keita, Assistant Professor, Behavioral and Social Sciences
Co-PI(s): Kim Gans, Professor, Department of Human Health and Family Studies, University of Connecticut; Alison Tovar, Assistant Professor, Department of Nutrition and Food Sciences, University of Rhode Island
Collaborators: Amy Nunn, Associate Professor, Behavioral and Social Sciences and Executive Director, Rhode Island Public Health Institute; Gemma Gorham, Project Director, Rhode Island Public Health Institute; Channavy Chhay, Executive Director, Center for Southeast Asians
Optimizing HIV pre-exposure prophylaxis (PrEP) uptake & adherence among stimulant using MSM
Men who have sex with men (MSM) are at elevated risk of HIV acquisition in US, and the number of new HIV diagnoses among this group is increasing annually. Similar trends have been seen in Rhode Island, with nearly 60% of incidence infections occurring among MSM. Problematic stimulant (crystal methamphetamine, cocaine and crack) use is a prevalent (20-times that of the general-population) and treatment-refractory problem in MSM, and highly predictive of HIV acquisition via an increased number of male sexual partners and frequent, prolonged, condomless sex. Several RCTs and demonstration projects provide strong evidence for the efficacy of a once-daily oral pill (emtricitabine/tenofovir) as pre-exposure prophylaxis (PrEP) for the prevention of HIV among uninfected, at-risk individuals, including MSM. The efficacy of PrEP is highly dependent on excellent adherence. Preliminary studies from our group document that MSM with stimulant use disorder are very interested in using PrEP (>90%), but their greatest reported-concern is that their drug use would lead to suboptimal adherence. Overview/Next-Steps: Providence is primed to be a site for developing and pilot-testing a PrEP adherence intervention for MSM with stimulant use disorder, with one of the first clinical PrEP programs in the country, led by our team at Miriam Hospital/Brown University. Informed by over a decade of formative research and addiction treatment experience with stimulant-abusing MSM, our interdisciplinary investigator team designed the "Pepped on PrEP" package - a counseling and problem-solving PrEP adherence intervention that addresses stimulant-abuse, and associated factors, as barriers to optimal adherence. We propose a pilot-RCT to assess the feasibility/acceptability of the "Pepped on PrEP" package, laying the groundwork for the next step of intervention development/testing--an NIH R01 efficacy trial.
PI: Matthew Mimiaga, Professor, Behavioral & Social Health Sciences, Epidemiology, and Psychiatry & Human Behavior
Co-Is: Philip Chan, Assistant Professor of Medicine; Kenneth Mayer, Professor of Medicine, Harvard Medical School; Adjunct Professor of Epidemiology and Medicine, Brown University
Development of on-site helium liquefaction for study of physical property of advanced materials and enabling novel applications
This Seed award will help with installation of a helium liquefier system. The liquefier is essential to provide a reliable and inexpensive supply of liquid helium, indispensable for achieving low temperature environment in which quantum effects can be studied and exploited to develop truly novel devices and sensors. Specifically, the proposed research focuses on investigation of emergent quantum properties in advanced materials and in quantum fluids; and, on development of high frequency transport measurements, high frequency devices, and sensors for astrophysical applications. Currently, due to the extremely high cost of liquid helium, a small part of this research is carried out at the National user facilities where very limited time is available for the experiments. Working at external facilities extremely limits our scientific productivity and creativity, i.e. ability to collect preliminary data. Thus, the most important aspect of helium availability is that it will allow us to collect preliminary data on many novel projects at nearly no cost. The ultimate results of this initial effort are development of unique, cutting-edge experimental capabilities and formation of competitive collaborative teams that will revolutionize the physical sciences at Brown. In addition, our efforts will open up new research opportunities for Brown’s materials and devices research programs, and will allow us to seek numerous new funding opportunities. With access to essentially cost free liquid helium, the investigators will be able to perform world-class leading research that is currently impossible to conduct at Brown due to the excessive cost and lack of reliable supply of helium.
PI: Vesna Mitrovic, Associate Professor, Physics
Co-PIs: Jim Valles, Professor, Physics; Humphrey J. Maris, Professor, Physics; Gregory Tucker, Professor, Physics;Alexander Zaslavsky, Professor, Engineering and Physics
Engaging the Chinese Lunar Exploration Program (CLEP): A Short-Term Investment with Long-Term Payoffs for Brown University
Faculty, students and staff from Brown University have historically been intimately involved in robotic and human Solar System exploration through active participation in experiments and space missions flown by the United States, the Soviet Union, Russia, the European Space Agency, India, and Japan. In the last decade, the People’s Republic of China has emerged as a major power in space exploration, launching astronauts into Earth orbit, building an Earth-orbiting space station and sending several very successful robotic missions to the Moon, with the ultimate goal of human lunar landings in the 2030s. U.S. Government guidelines have inhibited detailed NASA interactions with China but this attitude is changing rapidly as policy-makers seek ways for peaceful engagement. This period of transition represents a major opportunity for Planetary Geoscientists at Brown University. Here we describe a series of steps in the coming year that will position Brown University for future NASA funding for foundational engagement in the Chinese Lunar Exploration Program (CLEP) for the next two decades. These steps, based on our very successful 40+ year engagement with the Soviet Union/Russia, are four-fold: 1) Establish individual contacts with the key scientific personnel in the Chinese Lunar Exploration Program, 2) Outline a scientific strategy and plan of mutual interest, 3) Prepare robotic and human landing site selection and operations strategy documents that would form the core of the interactions, 4) Provide a sound and concrete basis for future proposals to NASA and the Chinese government for engagement in the Chinese Lunar Exploration Program.
PI: James Head, Professor, Earth, Environmental and Planetary Sciences
Prospective Brown-NUWC Collaboration to Develop New Sensor Materials for Underwater Acoustic Sensing
This Seed award supports novel research on materials never before used for flexible pressure and acoustic sensing, for which we plan to seek for external funding in partnership with the Naval Undersea Warfare Center (NUWC) at Newport, RI. While the PI's group is a recognized leader in nano-engineered new materials, its past experience and existing experimental capabilities have been on the mm to nm scale, much smaller than the scale, m to cm, needed by NUWC for applications in undersea sensing. To bridge this gap, we propose a pilot effort to scale up our fabrication and opto-acoustic characterization capabilities, by 10x, to the cm scale to prove the feasibility of scaling the base process while still leaving the more costly larger scale engineering-implementation to the better equipped and financed hands at NUWC. The proposed tasks for the collaborative effort between NUWC and Brown, that is anticipated to follow the Pilot project, are outlined below along with a projected pilot project cost breakdowns for FY16. These technologies offer a means for the use of new sensing materials that are applied for underwater acoustic sensing in a hydrophone device. These technologies offer flexibility, tunability, optical clearity, and conformal advantages that can be tailored for a number of other advantageous undersea applications.
PI: Jingming (Jimmy) Xu, Professor, Engineering and Physics
Co-PIs: Naval Undersea Warfare Center
Humanities & Social Sciences
Mapping Violence: Visualizing Histories of Loss
This award will support the development of an interactive platform that recovers and makes visible lost and obscured histories of racial violence in Texas from 1900 to 1930. This project grew through collaboration between the primary investigator and the John Nicholas Brown Center for Public Humanities at Brown University. Mapping Violence will enrich current understandings of histories of racial violence in the humanities, offer a model for using digital technology to present findings in the humanities to wider publics, engage educators and wider publics with this under-explored historical topic, and help advance Brown's reputation as a leader in developing digital humanities projects. Mapping Violence addresses fundamental questions on the best practices for visually representing histories of racial violence to a broad audience. How does one map a history of loss? This interdisciplinary project is at the intersection of ongoing conversations in the fields of American Studies, US History, Ethnic Studies, Digital Humanities, and the Public Humanities that explore how best to narrate histories of racial violence in the United States. A Seed award will fund two advanced graduate student research assistants and two undergraduate research assistants to expand and prepare the project database for production. The research team will take one trip to Texas for archival research and develop curated content for the platform. The award will advance a future application for a National Endowment for the Humanities Digital Projects for the Public Production Grant.
PI: Martinez, Monica, Assistant Professor, American Studies
The Rise, Spread, and Consequences of the Common Core State Standards Initiative in the U.S. Education Sector
The Common Core State Standards Initiative, launched in 2008, marks an historic attempt to improve the quality of instruction in American public schools, to reduce inequality in instruction, and to bring coherence across states and systems of schooling. Our interdisciplinary, multi-institutional team from Brown University, the University of Michigan, and Stanford University will explore whether and how this landmark initiative is improving school system management, classroom instruction, and student achievement in diverse local settings; and if so, why. Over the course of our five year study, our team will assess the development and use of Common Core through panel surveys of nationally representative samples of teachers, ethnographic studies of classroom practice, comparative cases of school systems in four states, and large scale data analysis of the determinants of student achievement over time. Our research program will not only provide the leading assessment of this historic initiative, but it will also establish new theoretical terrain on mechanisms of standardization in fragmented policy domains, challenge long-standing conventions used to measure state capacity, and reveal whether and how the development and diffusion of educational standards bears on inequality in American education. Seed funds will support a preliminary nationally representative survey of teachers and to support early interviews in our four case study states to help us prepare for and justify our multi-million dollar five year study.
PI: Susan Moffitt, Assistant Professor, Political Science
Co-PIs/Collaborators: David K. Cohen, John Dewey Collegiate Professor Ford School of Public Policy, School of Education, University of Michigan; Brian Rowan, Burke A. Hinsdale Collegiate Professor, School of Education, Institute for Social Research, University of Michigan; Sean F. Reardon, Professor, School of Education, Stanford University
Metatranscriptomic analysis to profile oral microbiome responses to broad-spectrum antibiotics during treatment of community-acquired pneumonia
The spread of antibiotic resistance is jeopardizing the efficacy of currently available antibiotics. Further complicating antibiotic therapy is a new awareness that antibiotic toxicity in non-pathogenic members of the microbiome can lead to detrimental health outcomes. To formulate therapies that have fewer complications we need to understand how untargeted bacteria respond to treatment. Metatranscriptomic analysis can profile responses in these off target bacteria and identify which bacteria are directly impacted by broad-spectrum antibiotics. We hypothesize that the differential regulation of antibiotic tolerance and resistance mechanisms can be used as a fingerprint to identify members of the microbiome that are impacted by antibiotic treatment. By conducting a community wide transcriptomic analysis of microbial populations with and without antibiotic treatment we can link well-established antibiotic response mechanisms to treatment outcomes. The key strength of this approach is that it can test antimicrobial perturbations in situ. Our initial focus will be on the oral microbiome of community-acquired pneumonia patients undergoing antibiotic treatment at Rhode Island Hospital. For this Seed project we have assembled a team that is uniquely suited to undertake this work, combining expertise in clinical infectious disease with microbiology and bioinformatics. The preliminary data and expertise obtained as part of this project will be a critical seed for the development of further work and funding opportunities. Finally, by developing sequencing and computational pipelines this project will develop capacity at Brown to study microbial flora in the context of infectious disease.
Assembling Complete Genomes Through Early Access to Nanopore DNA Sequencing
Despite the declining cost and increasing volume of highthroughput gene sequencing, it is still difficult and expensive to sequence and assemble genomes. Recently, we won competitive access to the initial release of a new nanopore sequencing technology (MinION) that has the promise to costeffectively read ultralong DNA fragments. These longer fragments are critical to successfully assembling complete genomes from scratch, and individual reads could potentially capture entire chromosomes. Leveraging this early access, we will research both the DNA preparation methods and data analysis methods needed to realize this promise, with immediate applications to our existing genomics projects. This interdisciplinary research will draw on expertise in biochemistry, computation, and statistics to tackle three key challenges: preserving ultralong DNA sequences so that they can be sequenced in their entirety by nanopre devices,; characterizing the signal space of the nanopore device and devloping statistical methods that align and assemble these signals; and testing hybrid assembly methods that combine nanopore sequence data with other highthroughput sequence data to assemble larger metazoan genomes. The preliminary methods and data generated by this work will enable new proposals for external funding in our groups and respective departments and strengthen pending proposals. The new computational methods developed here could result in a patent for Brown. Moreover, this work will establish a new DNA sequencing resource at Brown that will complement the existing Genomics Core Facility, can be shared by other labs with similar genomics projects, and will lead to further collaborations and funding opportunities.
PI: Susan A. Gerbi, Professor, Molecular Biology, Cell Biology and Biochemistry
CoPIs: Mark Howison, Director of Data Science, Computing and Information Services
Charles Lawrence, Professor, Division of Applied Mathematics
Benjamin J. Raphael, Associate Professor, Computer Science
Tissue Engineering for Personalized Medicine – 3D Human iPSC-Neuronal Microtissues
Modern drug development requires drug discovery, testing, and validation. It is costly and inefficient, and after drugs are brought to market, many fail. The goal of this project is to develop three-dimensional (3D) microtissues composed of patient-specific neural cells, in order to develop patient-specific disease modeling, drug testing and personalized medicine. Advantages of this approach are clear. Safety and efficacy studies on human cells can increase the likelihood of success in drug targeting. 3D cultures replicate the in vivo environment better than two-dimensional (2D) cultures, and as such, will provide more authentic assays for testing. We focus on the nervous system because there is an unmet need for fully comprehending and developing truly successful therapeutics for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. This interdisciplinary team brings to bear the approaches of stem cell technology, neuroscience, neurophysiology, and tissue engineering on these complex problems. They will generate patient-specific neurons from human induced pluripotent stem cells (hiPSCs), including those from patients with Christianson syndrome and from their unaffected siblings. These neurons will be placed into high-throughput 3D cultures. hiPSC-neurons’ abilities to express key characteristics of neurons, including synaptic connections, will be confirmed, and their response to various drugs and disease assays will be explored. At the conclusion of this study, we will have key data to secure external funding for large-scale studies in these critical fields of research, and we will advance Brown’s position in the cutting- edge areas of pharmacogenomics and personalized medicine.
PI: Diane Hoffman-Kim, Associate Professor, Molecular Pharmacology, Physiology, and Biotechnology
Co-Investigators: Julie Kauer, Professor, Molecular Pharmacology, Physiology, and Biotechnology
Eric Morrow, Assistant Professor, Molecular Biology, Cell Biology and Biochemistry; Psychiatry and Human Behavior
Climatic and Environmental Reconstruction Using Lipid Biomarkers in Ancient Bones: Applications in Archaeology, Paleoclimatology and Paleontology
This proposed research builds on a recent exciting discovery of Professor Huang’s research group that a key class of climate-sensitive bacterial lipid compounds, is abundantly and well preserved in ancient bones. Ample research in the past few years has demonstrated that the molecular distribution of these bacteria-derived compounds in the environment faithfully records temperature and, in relatively dry regions, precipitation. Our discovery opens up a promising new avenue to extract paleoclimatic and paleoenvironmental information directly from animal or human bone samples, eliminating the key problem in environmental archaeology and paleontology of correlating such evidence directly to find contexts. Using the seed funds from Brown, we intend to demonstrate the efficacy of the new approach by analyzing a critical set of recent to modern bone samples across major climatic and environmental gradients; perform initial laboratory experiments to determine the time required for signatures to be fully registered upon bone burial in soil at controlled temperatures; analyze bone samples from important archaeological time intervals to obtain proof-of-concept data. A successful initial study as we propose here, will generate critical data with a major interdisciplinary impact that enable rapid publication of these innovative and original research technologies; they will in turn also pave the way for large collaborative research proposals across several departments at Brown to the NSF and other agencies.
PI: Yongsong Huang, Professor, Earth, Environmental, and Planetary Sciences
Co-PIs: Peter van Dommelen, Professor, Joukowsky Institute for Archaeology and the Ancient World
Andrew Scherer, Assistant Professor, Anthropology
Kevin Smith, Deputy Director and Chief Curator, Haffenreffer Museum of Anthropology
Engineering Orthogonal Ribosomes to Study Ribosome Function
The ribosome is the macromolecular machine responsible for the translation of genetic information in all forms of life. Over half of all antibiotics target the ribosome, and many are thought to act by interfering with ribosome conformational transitions. Thus deciphering the dynamic nature of the ribosome is important both for achieving a deeper understanding of a fundamental aspect of biology and for the rational design of new antibiotics. In our research collaboration, we will combine genetics with X-ray crystallography to determine the structures of ribosomes frozen in intermediate states by mutations at key functional sites. However, because the ribosome is an essential cellular component, the most informative mutations are expected to be lethal. Here, we propose to develop an orthogonal ribosome system to study ribosomes with otherwise lethal mutations. We will construct bacterial strains in which a subset of ribosomes has been altered to only translate one or more orthogonal reporter messenger RNAs. This system enables the production of ribosomes that would otherwise be toxic for the organism. The presence of compatible orthogonal reporter mRNAs and the insertion of an affinity tag further enable functional characterization in vivo as well as biochemical and crystallographic studies of these orthogonal ribosomes. After completion of the proposed work, we will be in position to submit applications to fund the long-range goals of this research program, determining the structures of ribosomes with mutations affecting conformational dynamics.
PIs: Gerwald Jogl, Associate Professor, Molecular Biology, Cell Biology and Biochemistry
Steven Gregory, Associate Professor (Research), Department of Molecular Biology, Cell Biology and Biochemistry
Exploring Innovative Delivery Methods for Brief Alcohol Interventions: The Electronic Mobile Alcohol Interventionist (EMAI)
We seek to prototype and evaluate an Electronic Mobile Alcohol Interventionist (EMAI), a robotic system that interacts with college students and helps them consider decreasing unhealthy drinking behaviors. The work is motivated by existing studies that show that robotic systems engender greater compliance than their on-screen counterparts and, at the same time, greater cost-effectiveness than therapies that require face-to-face interactions with trained experts. As a pilot study, we hope to replicate these results in an important concrete therapeutic context, specifically alcohol intervention. If successful, the project will open up opportunities for the team to seek grants at the boundary between the behavioral sciences and robotics, where novel behavioral therapies are joined with powerful new autonomous decision making algorithms to help improve health in a cost-effective manner.
PI: Michael Littman, Professor, Computer Science
Co-PI: Christopher Kahler, Professor, Behavioral and Social Sciences
Engineering Cell Morphology and Phenotype using Bioinspired Graphene Nanoarchitectures
Interactions between mammalian cells and nanoscale topographies represent an important but poorly understood signaling modality. In particular, the extracellular matrix (ECM) presents nanoscale architectural features that can direct cellular form and function, particularly during epithelial tissue remodeling and macrophage inflammatory responses. Remarkably, modern nanofabrication techniques enable artificial structures with sizes and geometries comparable to those found in the ECM. Here, we propose to explore the role of topographically patterned graphene oxide on cell morphology and phenotype. We will apply thin, stiff graphene oxide sheets to softer elastomeric substrates to generate periodic wrinkling patterns. We hypothesize that anisotropic geometries lead to the alignment and elongation of epithelial cells and macrophages. These biased nanoarchitectural cues may then alter gene expression to perturb cellular phenotype. We envision that this project will inspire new directions in nanomechanics with applications in stretchable electronics, energy storage and functional coatings. Moreover, this project will lead to new fundamental insights into how cell behaviors are modulated during embryonic development, wound healing, inflammation and cancer, with applications in designer biomaterials and regenerative medicine.
PI: Ian Y. Wong, Assistant Professor, School of Engineering; Molecular Pharmacology, Physiology and Biotechnology
Co-PIs: Agnes B. Kane, Professor, Pathology and Laboratory Medicine
Robert H. Hurt, Professor, School of Engineering
Nanoimprinted Nanowire Solar Cells
The eventual long-term goal of this research program is to create a cost-effective high-density nanowire (NW) solar cell that will exceed the so-called Shockley-Queisser power efficiency limit of ~29% for single-junction, single-crystalline silicon solar cells. The nanowire platform makes it possible to create multi-junction solar cells involving multiple materials that absorb more of the solar spectrum over a far smaller vertical cell thickness, resulting in lighter, more efficient cells. While both NWs and NW arrays have demonstrated impressive performance in the laboratory recently, cost-effective heteronanowire integration remains to be demonstrated. We have recently combined nanoimprint lithography, which permits effective fabrication of high-density (~500 nm pitch) arrays, with epitaxy (at NIST) of < 200 nm diameter Si nanowires to fabricate high-density solar cell arrays with improved efficiency over lower-density arrays grown from the usual vapor-liquid-solid (VLS) method using randomly dispersed metal seeds. Our three-dimensional finite-difference time-domain simulations show that due to diffractive scattering and light trapping, an array with 250 nm pitch should significantly outperform a blanket Si film of the same thickness – a result we plan to demonstrate experimentally during the next 6–9 months. At the same time, the small diameter of our NWs permits the combination of lattice-mismatched Ge/Si NW sections – an enabling technology for tandem Ge/Si NW solar cells combining reduced reflection with better solar spectrum coverage. The seed grant will strengthen the existing collaboration between the PIs and a National Laboratory, positioning the Brown-led team for success in extramural funding.
Asia-Pacific in the Making of the Americas: Resources for Study
Begun three years ago by a group of Brown faculty and fellows working at the John Carter Brown Library (JCBL), the “Asia‐Pacific in the Making of the Americas: Toward a Global History” project has held six interdisciplinary, international symposia focused on transpacific interactions 1500‐1900. This Seed award will move the project to the next phase, to solidify the cohort of participating scholars through a digital publication and archive on the Brown Digital Repository. An ongoing collaboration will be established among Brown’s departments of History, English, American Studies, the Brown University Libraries and the JCBL to produce a digital multi‐authored publication that includes an archive of primary resources. This work entails close collaboration with librarians in the Center for Digital Scholarship and the JCBL. The Seed team will design and build the website using primary resources in the Brown Libraries and contributed essays, and will forge agreements with international institutional partners to add new materials to the site in the future.
PI: Evelyn Hu-DeHart, Professor, History & American Studies
Co-PIs: Caroline Frank, Visiting Assistant Professor, American Studies
Jim Egan, Professor, English
Librarians: Andy Ashton, Associate University Librarian for Digital Technologies
Elli Mylonas, Senior Digital Humanities Librarian
Jean Bauer, Digital Humanities Librarian
Rhode Island Child Obesogen Study-Pilot Phase*
Childhood obesity is the greatest public health threat to the current generation of United States children, and the identification of modifiable risk factors to prevent this epidemic is urgently needed. Prenatal insults may increase the risk of obesity by disrupting hormonally controlled mechanisms including adipogenesis, appetite, or epigenetics. Endocrine disrupting chemicals are a class of potential ‘obesogens’ that perturb these mechanisms and may increase the risk of obesity and cardiometabolic disorders. This project will build on the research infrastructure at Women and Infants Hospital Primary Care Center to conduct a pilot study and enroll 100 pregnant women at their first prenatal care clinic visit, and follow them and their offspring until delivery. Prenatal exposure to suspected contemporary endocrine disrupting obesogens will be measured. In addition, this study will measure biological intermediates involved in the development of obesity that are susceptible to endocrine disruption and associated with newborn adiposity. To ensure the associations between chemical obesogens and infant adiposity are independent of other important prenatal determinants of childhood obesity, this study will assess maternal diet, physical activity, psychosocial status, neighborhood level factors, and socioeconomic position. This cohort will serve as a resource to other Brown investigators interested in studying prenatal determinants of child and adult health.
Co-PIs: Joseph Braun, Assistant Professor, Epidemiology
Erika Werner, Assistant Professor, Obstetrics and Gynecology
Co-Investigators: Nicola Hawley, Research Fellow in Clinical Psychology
Karl Kelsey, Professor, Epidemiology & Pathology and Laboratory Medicine
Stephen McGarvey, Professor, Epidemiology & Anthropology
Maureen Phipps, Professor, Epidemiology & Obstetrics and Gynecology
Megan Romano, Postdoctoral Research Associate, Center for Environmental Health and Technology
David Savitz, Professor, Epidemiology & Obstetrics and Gynecology
Empower, Nudge: Increasing Dual Protection among Young Women in South Africa*
The overarching goal of this project is to reduce unintended pregnancies and sexually transmitted infections among young South African women, aged 18-30, who are defined as high-risk for unintended pregnancy and HIV acquisition. The main hypothesis is that a simple delivery innovation, when combined with health promotion strategies derived from behavioral economics, will motivate women’s greater uptake of effective contraception, and more consistent use over time. The specific objective is to test this hypothesis on a small-scale, in an urban setting in South Africa. This project will test a service delivery innovation, the “mini-packet,” and two kinds of innovative behavioral-economic incentives to promote initiation and adherence to voluntary contraception. A three-arm experiment in which the contraceptive packet alone will be compared against the contraceptive packet plus a loss-regret strategy (lottery), and the packet plus a standard (fixed) economic incentive will be piloted. A team of researchers from Brown and University of Cape Town (UCT) will deepen and extend cross-institution links though this multidisciplinary endeavor that incorporates distinct but overlapping research areas: behavioral and health economics, epidemiology, social and behavioral science, and behavior change.
PI: Omar Galárraga, Assistant Professor, Health Services Policy and Practice
Co-PI: Abigail Harrison, Assistant Professor (Research), Behavioral & Social Sciences
Co-Investigators: Mark Lurie, Assistant Professor, Epidemiology and Medicine
Kathleen Morrow, Associate Professor (Research), Psychiatry & Human Behavior and Behavioral and Social Sciences
Susan Short, Professor, Sociology
Brendan Maughan-Brown, Department of Economics, University of Cape Town
Scaling Evidence-Based Medicine via Automation and Crowdsourcing*
Evidence-Based Medicine (EBM) aspires to inform clinical care with all available evidence. The most important tool in the EBM arsenal is the systematic review, which provides an unbiased, comprehensive, (usually) quantitative summary of the evidence regarding a clinical question.Figure: Three sets of annotations for the same abstract. Here we have color-coded tagged words. Same color for the same word means agreement between reviewers. Annotations include (total) study sample size, treatment names and group sample sizes.
Producing such reviews requires exhaustively identifying relevant articles and extracting from these the data to be synthesized. These tasks have become increasingly onerous as the biomedical literature base has exploded in recent years. This Seed team will capitalize on research strengths unique to Brown in big-data, crowdsourcing and EBM, and will represent the first effort to crowdsource systematic reviews. This project will investigate the application of novel technologies (crowdsourcing, automation and hybrid strategies combining them). This research thus has the potential to greatly optimize the conduct of systematic reviews. Moreover, the proposed approach of algorithmically combining domain expertise with low-cost human computation and automation to perform high-quality work at low cost is novel from a Computer Science perspective and will have wide application. This team will procure crowdsourced annotations for two systematic review tasks. This data will be used to assess the viability of crowdsourcing for systematic reviews, and to evaluate initial hybrid human/computer strategies.
PI: Byron Wallace, Assistant Professor (Research), Health Services, Policy & Practice
Co-PIs: Thomas Trikalinos, Associate Professor, Health Services, Policy & Practice
Tim Kraska, Assistant Professor, Computer Science
Ugur Cetintemel, Professor, Computer Science
Robot Telepresence in Improved Nursing Home Organization*
Robotics is poised to be a groundbreaking technology with the potential to drastically improve outcomes, increase access, and decrease costs for healthcare. The development of smart services to care for and engage our aging population is a critical need, especially the most vulnerable and expensive-to-care-for nursing home residents. While the benefits of robotic telepresence for individual older adults have been explored, it remains unclear how effective this technology will be when scaled to the level of a nursing home. Open empirical questions revolve around the level of acceptance of these systems by the residents, staff, and administrators of these facilities, as well as their feasibility within existing facility procedures. This pilot project will study the efficacy of networked robotic services in improving the processes and organization of nursing homes and the care of older adults. The Seed team will explore the effect of using commodity robot telepresence systems for more efficient and costeffective care through telemedicine. Resulting projects will address open questions along the social, empirical, computational, engineering, design, and cost-benefit dimensions of robot telepresence in nursing homes.
PI: Odest Chadwicke Jenkins, Associate Professor, Computer Science & Engineering
Co-PIs: Michael Littman, Professor, Computer Science
Richard Besdine, Professor, Medicine & Health Services, Policy and Practice
Terrie Fox Wetle, Dean, School of Public Health
Non-Invasive Measurement of Mechanical Properties of Biological Materials
Biomimetic research studies the underlying structure and function of biological materials in order to create better biologically inspired structural materials. Hierarchical structure lies at the core of the enhanced mechanical performance of biological materials such as the strength of seashells, the elasticity of spider silk, and the crack-resistance of biological sea sponge. This project seeks to understand the structure-function connection in some of nature's archetypal structural materials ultimately achieving complete understanding of the design principles underlying natural materials to make better, stronger, tougher materials. This team will collect preliminary data by investigating the mechanical properties of the basalia spicules in the marine sponge Euplectella Aspergillum using laser light scattering spectroscopy and correlating it with theoretical and computational modeling. This unique approach will provide noninvasive, spatially resolved measurements of the in situ mechanical properties of individual components in these hierarchical structures. This information will be used to create models to explain the enhanced properties of the composite. Having established the methods with sponge spicules, this team will be positioned to expand the scope of the project into other materials.
Co-PIs: Kristie Koski, Assistant Professor, Chemistry
Haneesh Kesari, Assistant Professor, Engineering
Blindfind: Empowering the Blind to Independently Navigate Public Indoor Environments*
The BlindFind system leverages the accelerating pace of discovery in computer vision and mobile computing power for the benefit of visually impaired citizens. The project will develop a working prototype of a wearable computer-vision system and complementary geo-location mapping data repository to assist the visually impaired as they navigate public indoor environments. The BlindFind system will consist of small cameras mounted on eyeglasses, a haptic belt, an Inertial Measurement Unit worn on the belt, and a bone-conduction headphone set – all connected to a small laptop carried in a backpack. A visually impaired user equipped with BlindFind will first pilot the system in a new building with sighted assistance. The user will document key points of interest and annotate a map of the space, while the system stores and overlays landmark information within a central repository of location-specific data. Future users of the system will benefit from the annotation and other stored data; they will be presented with verbal and haptic information to guide them when they interact with the system through an audio menu. The system will respond by issuing verbal guidance and navigation assistance as necessary.
PIs: Benjamin Kimia, Professor, Engineering
Pedro Felzenszwalb, Associate Professor, Engineering & Computer Science
Enabling Autonomous Flight of Drones in Complex, Unpredictable Environments*
Tropical forests are diverse, and much of this diversity is supported by the canopy. To better understand this diversity requires better characterization of the canopy, yet no present technology allows repeatable, direct, interactive observation within and around complex canopies. Unmanned aerial vehicles (UAVs), hold great promise, but there are formidable challenges to navigating UAVs in these complex environments. What is needed is sophisticated onboard processing that characterizes the environment in 3D and makes decisions in real time about its operation in order to achieve a given objective. Existing technology is far too costly and heavy for small aircraft, and the energy requirements do not allow the UAV to operate for more than a very short period of time. This project will develop new computing solutions for real-time navigation of UAVs in these complex environments. The challenge is to use a combination of software algorithm development, customized hardware design to accelerate these algorithms, and novel design space exploration techniques that produce solutions that carefully balance navigation accuracy, system energy consumption, and realtime response rate together. The results could be generalized beyond the tropical forest, wherever real time compute-intensive processing is needed in highly constrained environments.
PI: R. Iris Bahar, Professor, Engineering
Co-PIs: Sherief Reda, Associate Professor, Engineering
James Kellner, Assistant Professor, Ecology and Evolutionary Biology
Odest Chadwicke Jenkins, Associate Professor, Computer Science & Engineering
Genome-wide sequence analysis in severe autism and intellectual disability
Autism is a relatively common cognitive development disorder that is associated with profound costs for society and families. In particular, a cohort referred to as “difficult-to-treat autism” (DTT-Autism) shows no or minimal improvements in the context of current interventions. Recent progress in genetics has highlighted the role of rare and de novo genetic variation in the development of autism, pinpointing overall mutation burden as well as numerous heterogeneous and individually rare loci. The central hypothesis of this proposal is that DTT-Autism may be sub-divided into distinct sub-diagnoses based on whole-genome sequencing (WGS) and genetic network analysis. This proposal describes two main areas of investigation: (1) WGS will be performed, which we anticipate will uncover individual genetic causes relating to DTTAutism, including potentially treatable metabolic disorders. This will guide current use of WGS in autism diagnosis. (2) Novel algorithms emerging from this team will be applied to WGS data to identify challenging-to-find variants and genetic combinations associated with DTT-Autism. This project will result in the generation of a substantial volume of sequence data that will be made available to investigators within Brown University and at surrounding Rhode Island hospitals for analysis and application to their specific research interests.
PI: Eric Morrow, Assistant Professor, Molecular Biology, Cell Biology and Biochemistry & Psychiatry and Human Behavior
Co-PI: Sorin Istrail, Professor, Computer Science
Creating a Providence-based Working Group in Precision Medicine to Identify the Genetic Determinants of Marijuana Sensitivity
This pilot technology development project will create a precision medicine working group in Providence, Rhode Island and generate preliminary data for a multi-investigator grant submission to NIH. The precision medicine working group will be organized around the problem of discovering genetic modifiers and pathways that influence the complex set of physiological/behavioral responses to Tetrahydrocannabinol (THC). The strategy will be to apply novel genomic technologies for the simultaneous sequencing and screening of genomic variants in NIDA funded study participants. The working group will leverage existing clinical histories, patient panels, DNA storage arrangements, IRB approvals, and protocols for maintaining patient contact and confidentiality. This existing clinical infrastructure is complemented by functional and computational genomics expertise. Seed funds will catalyze the collaboration between the investigators by performing exome sequencing, annotation and functional data on each variant’s effect on gene processing to create the first individual(s) genome(s) that have been characterized at a functional level.
PI: Will Fairbrother, Associate Professor, Molecular Biology, Cell Biology & Biochemistry
Co-PIs: Valerie Knopik, Associate Professor (Research), Psychiatry and Human Behavior & Behavioral and Social Sciences
John McGeary, Assistant Professor, Psychiatry & Human Behavior
Multispectral Photoplethysmography for 3D Imaging and Quantitative Assessment of Blood Flow and Oxygen Content in Bone*
The long-term goal of this project is to develop optical techniques with which to characterize important physiologic parameters non-invasively by exploiting the interaction of light with human tissues. The specific aim is to develop a photon-based device with functional capabilities for real-time, non-invasive, quantitative measurement and, ultimately, 3D imaging of blood flow and oxygen content in bone. The proposed device will consist of a flexible, planar matrix of densely integrated light emitting diodes (LEDs) and photodetectors (PDs) used to map, non-invasively, the blood flow and oxygen content in bone. The proposed project will lead to a clinically relevant technology and associated device, namely a system for 3D Multispectral Photoplethysmography Imaging (3D-MPPGI), enabling the noninvasive, quantitative description of physiologic and pathophysiologic characteristics and facilitating the early diagnosis of diseases such as osteoarthritis (OA) among other diseases of bone. This program will place Brown at the forefront of this innovative technology by creating a device that would become the state-of-the-art for measurements of circulatory physiology in tissues and would have wide-ranging clinical relevance.
PI: Domenico Pacifici, Assistant Professor, School of Engineering
Co-PI: Roy Aaron, Professor, Orthopaedics & Molecular Pharmacology, Physiology, & Biotechnology
Using big data to crack the neural code*An interface developed in the Serre lab to annotate objects and people using computer vision techniques with minimal human supervision.: A TV series is shown to an epileptic patient. The large-scale annotation of such movies combined with machine learning technique for neural decoding enables us to relate brain activity to audio and visual content. Photo Courtesy of Zach Nado
The goal of this project is to understand how the cortex processes sensory information during natural everyday perception. Epileptic patients with implanted intracranial electrodes offer a unique opportunity to collect neural data at both a high temporal and spatial resolution. Currently terabytes of neural data from these patients are being left unexploited because of the lack of appropriate tools to relate neural activity to natural unconstrained real world events. This team has developed new automated techniques for discovering perceptual and cognitive states during natural every day vision, and proposes to build the largest existing neural database consisting of hours of brain activity while participants watch TV together with semantic annotations of the corresponding audio and visual content. The team will make this data available to the Brown community and organize a Neural Decoding Grand Challenge. This project will catalyze the formation of interdisciplinary research teams at the interface between big data, neuroscience and computer science and build on Brown’s existing strengths to establish the university as the leader in brain mapping and neural decoding.
Co-PIs: Thomas Serre, Assistant Professor, Cognitive, Linguistic & Psychological Sciences
Nicholas Stevenson Potter, Assistant Professor, Neurology & Neurosurgery
Establishing a technique for studying the neural circuits underlying alcohol responses in flies
Understanding how activation of neural circuits elicits distinct behaviors is a daunting challenge. The Seed team brings together a leading expert in modeling alcohol responses in flies and the developer of Tango-trace, a technique for tracing circuits in flies. This project will utilize fruit flies to gain insight into the mechanisms underlying their complex behavioral responses to alcohol that are remarkably similar to the responses of mammals. Flies are the ideal model for studying the neural circuits underlying these responses because of the availability of sophisticated genetic tools for manipulating specific neurons and the ability to perform genetic screens to identify genes involved in this process. This project will establish a configuration of Tango-Trace for tracing the circuits necessary for generating long-lasting memory of intoxication. Tracing these circuits is critical for understanding (1) whether memories for aversion and reward are formed and retrieved through distinct, nonoverlapping circuits, (2) how the memory of alcohol intoxication is acquired, consolidated, and retrieved, and (3) where the output response is initiated.
PI: Karla Kaun, Assistant Professor, Neuroscience
Co-PI: Gilad Barnea, Assistant Professor, Neuroscience
*Supported through funds dedicated to following up on outstanding projects proposed during the Signature Academic Initiative process.
Opening the Archives: Access to Information, Memory, and Justice Thirty Years After the End of the Brazilian Military Dictatorship
In 2012, Brazilian President Dilma Rousseff signed an Access to Information Law, establishing guidelines for declassifying documents and opening archives containing information about human rights violations committed by the Brazilian dictatorship (1964-85). She also appointed a Truth Commission to investigate the state’s involvement in torture and repression. Green has developed a joint project with a Brazilian historian to facilitate greater access to U.S. documents on Brazil for researchers in both countries. In conjunction with the Brazilian and U.S. National Archives, this collaborative team will coordinate a group of twelve Brown and two Brazilian students that will digitize and index U.S. State Department documents on Brazil from 1960 to 1980 that will appear on websites in Brazil and at Brown. The team will also identify documents for the Truth Commission’s investigations. This effort reinforces Brown’s reputation as the leading U.S. institution focusing on contemporary Brazilian history.
PI: James N. Green, Professor, History and Portuguese & Brazilian Studies
Co-PI: Sidnei Munhoz, State University of Maringá, Paraná Brazil
Solar Power by Optical Frequency Rectification with Plasmonic Concentrators Coupled to Junctions of Doped Mott Insulators
An alternative paradigm for the conversion of solar energy to electricity makes use of the collective electromagnetic nature of solar radiation instead of individual photons as conventional photovoltaic devices do. The electric field of sunlight is first intercepted by a nanoscale antenna, and then the oscillating electrical current is rectified into a useful DC current. Optical-frequency rectification – in effect a crystal radio that runs on visible light instead of radio waves – avoids altogether the mismatch between the photon energy and the semiconducting bandgap that limits the conversion efficiency of conventional photovoltaic cells. Solar rectification thus has the potential to create a cheaper and more efficient method for the exploitation of sunlight and could lead to a paradigm shift in solar technologies. This team will design and build prototype devices that combine plasmonic concentrators / antennas with novel rectifying junctions of doped Mott insulators to test the feasibility of the concept. A working device will be a compelling argument for external funding.
Domenico Pacifici, Assistant Professor, Engineering
Gang Xiao, Professor, Physics
Three-dimensional Traction Mapping Distinguish Neutrophils from Healthy and Septic Donors
Neutrophils are the most abundant white blood cell in the circulation and are among the first cells to response to an injury or infection; they are essential for health. Patients with decreased numbers of circulating neutrophils, or with inherited defects in neutrophil functions, are susceptible to opportunistic infections and have impaired wound healing. Efforts to study neutrophils under physiologically relevant settings have found that these cells are highly sensitive to physical and biochemical cues that regulate the magnitude of the cellular response to an insult. In order to translate laboratory findings to a better understanding of how the cells function in vivo, this Seed team will study neutrophils in a three dimensional setting rather than on standard 2D surfaces. This synergistic effort between laboratories in the Departments of Surgery at Rhode Island Hospital and the School Engineering will investigate neutrophil tractions in native 3D collagen gels and quantify cellular differences between healthy and septic cells.
Phosphatase Inhibitor Design – A Unique Possibility for Brown University
The specific and reciprocal relationship between kinases and phosphatases controls most biological processes. Thus, when the balance is disrupted, the result is often disease. To date, efforts to modulate phosphate signaling to treat these diseases have focused on inhibiting kinases. However, it has recently become evident that the exquisite regulation of phosphorylation signaling is driven by tyrosine and serine/threonine phosphatases, rather than by kinases. Thus, one of the fastest growing areas of research is to identify potent, specific inhibitors of phosphatases. The Seed team will combine expertise in biochemistry, structural biology, biophysics and synthetic organic chemistry in order to develop novel, potent inhibitors of phosphatases. This project aims to develop novel peptomimetic inhibitors of the ser/thr phosphatase PP1 using data from multiple PP1 holoenzyme structures, molecularly characterize and optimize inhibitors that target the tyr phosphatase PTP1B, and develop new, potent immunosuppressant drugs using data from the ser/thr phosphatase calcineurin and chemical scaffolds already shown to target calcineurin.
Paul G. Williard, Professor, Chemistry
Making Sense of the Data Windfall: New Statistical Approaches to Evolutionary Analyses of Gene Expression
Many studies analyze gene expression to identify genes that play a functional role in particular biological processes. New tools make it possible to inexpensively measure the expression of all genes in a tissue sample. These tools, as applied in current study designs, are proving to be blunt instruments that turn up thousands of candidate genes for a particular biological process, most of which are erroneous by-catch. There is critical need to sharpen the focus of gene expression studies so that they identify a smaller set of more relevant genes. We propose to address this by adding an evolutionary dimension to gene expression studies. It will then be possible to identify speciﬁc genes that have evolutionary shifts in expression that are correlated with evolutionary changes in biological processes of interest. The hurdle to this approach is that statistical methods have not yet been developed, implemented, and tested for evolutionary analyses of high-throughput gene expression data. This project assembles an interdisciplinary team to do exactly this, and leverages Brown’s strong investments in genome sequencing and high performance computing.
PIs: Casey W. Dunn, Assistant Professor, Ecology and Evolutionary Biology
Xi Luo, Assistant Professor, Biostatistics
Zhijin Wu, Associate Professor, Biostatistics
The Role of Electrical Coupling Between Mitral Cells in Olfactory Coding*
Smell is the primary sense used by many animals to find food and mates and to avoid predators. Olfactory deficits in people are associated with loss of appetite, anhedonia and depression, and olfactory dysfunction can be an early sign of neurodegenerative diseases. The basic mechanisms by which the brain discriminates odors are obscure. Odors are detected by sensory neurons in the nose that project to special neurons called mitral cells. Patterns of mitral cell activity are transformed by the brain into the percept of a smell. Some mitral cells are electrically coupled through structures called gap junctions, also known as electrical synapses. This Seed team combines multidisciplinary expertise and the techniques of mouse genetics, electrophysiology, and behavioral analyses to study the role of electrical synapses in olfactory coding.
The Role of the Right Hemisphere in Speech and Lexical Processing*
Past research using a variety of populations and research methodologies has produced conflicting findings on the role of the right hemisphere in speech and lexical (word) processing. This project research aims to examine this question by analyzing the effects of right hemisphere lesions on speech and lexical processing in the context of current models of the functional architecture of language using state-of-the-art behavioral paradigms, measures, and neuroimaging techniques. This novel approach will add to the continued and growing strength of the Brain Sciences at Brown by contributing to the breadth of approaches used and potentially opening new directions of research examining language functions of the right hemisphere using functional neuroimaging and the application of basic research findings (bench) to language rehabilitation (bedside). Additionally, it will add a new recruiting site at the Rhode Island Hospital.
PI: Sheila E. Blumstein, Professor, Cognitive Linguistic & Psychological Sciences
Co-PIs: Lynn Fanella, MRI Senior Research Technologist/Manager
Karen Furie, Chair and Professor, Neurology
Kathleen Kurowski, Assistant Professor, Cognitive Linguistic & Psychological Sciences (Research)
John Mertus, Assistant Professor, Cognitive Linguistic & Psychological Sciences (Research)
Carole Palumbo, Boston University School of Medicine and VA Boston Medical Center
Development of New Computational and Point of Care Platforms for HIV Drug Resistance**
HIV drug resistance is a major cause of treatment failure. The ability to identify drug resistance is important in patient care, and identification of specific drug resistance mutations can assist in efficient regimen design. Resistance testing, required in developed countries, is rarely used in resource-limited settings due to financial and infrastructure constraints. This is a major hurdle in the fight against HIV/AIDS since the vast majority of this pandemic is in resource limited settings. This project builds on preliminary research and a newly-developed microfluidic method termed SMART (Simple Method for Amplifying RNA Targets), to be integrated into a point of care chip platform, for drug resistance detection in resource limited settings. This Seed team will develop a computational platform for global analysis of position-specific pol sequence variation across geographic regions within HIV1 subtypes, develop a SMART Microfluidic Platform to amplify and detect drug resistance in a full-length HIV1 plasmid, and validate the platform in HIV-infected patient samples.
Sorin Istrail, Professor, Computer Science
Joseph Hogan, Professor, Biostatistics
*Made possible through a generous donation of an anonymous donor
**Special Seed award for translational research
Climate Change, Biological Evolution, and Biogeochemical Cycles in Lakes of Central Sulawesi, Indonesia
The overarching goal of our research is to investigate coupled climatic, environmental, and biological evolution in central Indonesia over the last ~700,000 years. Indonesia lies at the heart of the Indo-Pacific Warm Pool, the largest pool of warm ocean water on Earth. Evaporation and rainfall over Indonesia controls the amount of water vapor in the Earth’s atmosphere and globally important climate processes such as the El Niño-Southern Oscillation. Long-term variations in Indonesian rainfall, combined with the tectonic evolution of the Indonesian archipelago, provide the environmental backdrop for the evolution of some of the most diverse ecosystems on Earth in Indonesia’s rainforests and lakes. We will investigate this variability by developing a Brown-led interdisciplinary science team to drill and analyze sediments from Lake Towuti, central Sulawesi, the largest lake in Indonesia.
PI: James Russell, Associate Professor, Department of Geological Sciences
Co-PIs: Anne Giblin, Senior Scientist, Marine Biological Laboratory at Woods Hole
Yongsong Huang, Associate Professor, Department of Geological Sciences
Stephen Parman, Assistant Professor, Department of Geological Sciences
Alberto Saal, Associate Professor, Department of Geological Sciences
Traffic Pollution and Acute Cardiovascular Events in Post-Menopausal Women
Cardiovascular disease is the leading cause of morbidity and mortality in the U.S. Wellenius will lead the first detailed study in a nationwide context of whether traffic pollution may increase the risk of cardiovascular events. This project will evaluate the association between long-term exposure to traffic pollution and cardiovascular risk within the Women’s Health Initiative (WHI), a large, national, prospective cohort study of 161,808 postmenopausal women. The proposed work is part of a broader research program to understand how different sources of ambient air pollution influence cardiovascular disease risk. The findings will likely have direct relevance on cardiovascular disease prevention by informing public health policy regarding the need for refinements to air pollution regulation, and position Brown University at the center of an exciting, important, and highly visible area of public health research.
PI: Gregory Wellenius, Assistant Professor, Department of Epidemiology
Co-PI: Charles Eaton, Professor, Departments of Family Medicine and Epidemiology
Eric A. Whitsel, Research Associate Professor, Department of Epidemiology, University of North Carolina Chapel Hill
Yi Wang, PhD, Post-Doctoral Research Associate, Department of Epidemiology
Melissa Eliot, PhD, Data Analyst/Programmer, Center for Environmental Health and Technology
Molecular and Cellular Mechanisms Underlying the Transition from Acute to Chronic Pain
Chronic pain is a serious health problem affecting millions of people in the USA alone. Chronic pain is highly prevalent in patients with diabetes, cancer, autoimmune deficiency, and following peripheral nerve injury. Strong evidence supports the theory that chronic pain is a maladaptive response of neurons to tissue injury or inflammation. The synapse is the site where neural transmission is scaled up and down in response to changes in neuronal input, but it is also now recognized as the critical pathological site in several brain diseases. Lipscombe and Kauer propose to begin to define fundamental cellular and molecular steps that support the development and maintenance of long-term changes in synaptic efficacy in the spinal dorsal horn, and then examine synaptic plasticity in the dorsal horn in animal models of chronic pain. The seed grant will allow them to garner preliminary data for future NIH applications.
PIs: Julie Kauer, Professor, Department of Molecular Pharmacology, Physiology, and Biotechnology
Diane Lipscombe, Professor, Department of Neuroscience
How Do Funding Mechanisms Affect Health Care Choices? Action for Health and Children’s Health in Mali
A key barrier to the cost-effective delivery of health care services in low-income countries is the lack of a full understanding of how families make decisions about when and where to seek healthcare. The aim of this project is to study these decisions in the context of children’s care. Sautmann and Dean will assess the relative importance of different factors that may affect the parents’ choice: financial constraints and costs; information and beliefs about the child’s need for care; and the preference of parents about trade-offs they must make e.g. between spending today and tomorrow, certain or uncertain outcomes or healthcare for their children versus other expenses. They frame their analysis in a dynamic model of healthcare decision-making, and use a randomized control trial of the “Action for Health” program of the Mali Health Organizing Project to estimate this model. The results will allow the researchers to predict changes in parents’ behavior and their impact on children’s health outcomes in response to different healthcare funding mechanisms.
PI: Anja Sautmann, Assistant Professor, Department of Economics
Co-PIs: Mark Dean, Assistant Professor, Department of Economics
Caitlin Cohen, M.D. Candidate, School of Medicine
The Impact of Agricultural Practices on Greenhouse Gas Emissions and Air Quality: A Case Study in New England
On a global basis, microbial activity in soils accounts for as much as 35% of nitrous oxide (N2O) emissions and nearly 20% of nitric oxide (NO) emissions. These trace gases are important in regulating Earth’s climate, while also influencing local air quality and acid rain deposition. Changes in N2O and NO emissions are anticipated with global changes in temperature, precipitation, and nitrogen fertilizer use, providing great potential for important feedbacks onto the climate and atmospheric systems. Hastings and Tang will develop a new system for automatically and simultaneously measuring the flux of N2O and NO from agricultural soils, and utilize this new technology in a pilot study to quantify the response functions of N2O and NO to parameters such as temperature, soil moisture, and nitrogen availability.
PIs: Meredith Hastings, Assistant Professor, Department of Geological Sciences and The Environmental change Initiative
Jianwu Tang, Assistant Scientist, Marine Biological Laboratory, the Ecosystems Center, and Brown Assistant Professor (MBL), Department of Geological Sciences.
Governance and Inequality in Indian Cities: A Seed Grant Proposal
Indian cities face tremendous challenges of governance because of entrenched inequalities and accelerating urban migration. Yet the social science literature on urban governance in India is conspicuous by its absence. This interdisciplinary team proposes to fill this gap through a long-term research project that is motivated by three fundamental questions. First, what are the predominant patterns of inequality in urban India and how is inequality structured? Second, how are Indian cities governed and how do these patterns of governance both reflect and impact patterns of inequality? Third, what forms of identity emerge in the migrant communities, as they come from villages to cities? And how do they view the state and fellow citizens? Who is us, who is them? This question, not often asked, is important for governance, for forms of consciousness have a relationship with what kinds of politics and political structures emerge, how political parties or civil society organizations mobilize citizens.
Novel Micropatterned Culture Model for Developing New Therapeutic Strategies for Sudden Cardiac Death
Sudden cardiac death is a leading cause of death in industrialized countries. It is most commonly caused by ventricular fibrillation, a fatal heart rhythm disturbance (arrhythmia). Emerging evidence indicates an important genetic contribution to sudden cardiac death; however, the molecular determinants have remained elusive. This project aims to develop a highly innovative and translational culture model of human cardiac arrhythmia by patterning cardiomyocytes derived from neonatal transgenic rabbits carrying a human mutation causing long QT type 2 syndrome, a common genetic cause for sudden cardiac death. Hoffman-Kim, Mende, Koren and Choi will use this new culture model to investigate arrhythmia formation, the mechanisms underlying the protective effects of progesterone as well as identify progestin molecules ideally suitable to prevent cardiac arrhythmias and sudden cardiac death in long QT syndrome.
PI: Diane Hoffman-Kim, Associate Professor, Department of Molecular Pharmacology, Physiology and Biotechnology
Bum-Rak Choi, Assistant Professor, Department of Medicine, Rhode Island Hospital
Gideon Koren, Professor, Department of Medicine, Rhode Island Hospital
Ulrike Mende, Associate Professor, Department of medicine, Rhode Island Hospital
Genetic, Biochemical, and Bioinformatic Approaches to Understanding Microbial Degradation of Plant Biomass
The development of renewable energy sources, which can supplant fossil fuels, is of utmost importance. As replacements for fossil fuels, biofuels are helping to meet the growing global demands for energy. The proposed research project will establish a conceptual framework for genetically engineering microorganisms to produce biofuels from plant biomass, a renewable and readily available source of carbon. Inspiration for this strategy comes from the abilities soil-dwelling microorganisms to degrade and consume plant biomass. We have assembled a research team with complementary and appropriate expertise to mine and elucidate the metabolic pathways for plant biomass consumption in soil-dwelling Streptomyces bacteria. By necessity, the project involves the synergistic application of experimental methods from genetics, biochemistry, computational biology, and chemistry.
PI: Jason Sello, Associate Professor, Department of Chemistry
Co-PIs: Rebecca Page, Assistant Professor, Department of Molecular Biology, cell Biology and Biochemistry
Charles Lawrence, Professor, Department of Applied Mathematics