The Foundation of Basic Research
Experimental investigation of disease mechanisms applies basic tools of cellular biology, biochemistry, and molecular biology to understand normal and abnormal cell and tissue function. The faculty in the Department of Pathology and Laboratory Medicine use state-of-the-art imaging and molecular approaches to study cell-cell interactions in reproductive biology and toxicology and molecular mechanisms of DNA damage and mutagenicity. At a biochemical level, other faculty focus on insulin and energy metabolism in the brain leading to neurodegenerative disease, changes in the blood-brain barrier, regulation of corticosteroid metabolism in hypertension and obesity, and biochemical markers for prenatal screening and prediction of adverse pregnancy outcomes. These basic researchers have also developed a variety of animal models of human disease including toxicant-induced testicular injury, fetal alcohol syndrome, and cancer related to asbestos exposure. Animal models are useful for developing novel therapeutic strategies for cancer and prevention of adverse reproductive and pregnancy outcomes.
Chemical, Structural, and Superstructural Determinants of Nanocarbon Toxicity
Principal Investigators: Agnes Kane and Robert Hurt
Professors Agnes Kane and Robert Hurt have teamed up to move Brown to the forefront of the study of toxicity in nanomaterials. Their mechanistic approach goes beyond simple assessment of toxicological endpoints to generate guidelines for manufacturing nanomaterials with minimal health impacts.
As a first step, Kane initiated an in vitro study of acute toxicological effects of model carbon nanofibers made by templating routes in the laboratories of Robert Hurt in the School of Engineering. A unique aspect of the work was the use of high-purity synthesis routes to make transition-metal free carbon nanomaterials of defined dimensions. This technique isolated the nanomaterials to better understand the physical determinants of their toxicity.
Molecular Mechanisms of Environmental and Occupational Toxicants
Principal Investigator: Kim Boekelheide
The research in the Boekelheide laboratory examines the fundamental molecular mechanisms by which environmental and occupational toxicants induce testicular injury. Current projects include the study of co-exposure synergy using model testicular toxicants, the biological basis of irreversible testicular atrophy, the role of in utero exposure to endocrine disruptors in the induction of testicular germ cell cancer, and the testing of human-relevant model systems for the response to anti-androgenic endocrine disruptors including phthalates.
DNA Repair, DNA Damage and Stress Signaling
Principal Investigator: Anatoly Zhitkovich
The Zhitkovich laboratory studies cellular stress responses that control DNA repair processes and cell fate decisions following DNA damage by carcinogenic chemicals and anticancer drugs. The primary research efforts are directed at the characterization of biochemical and genetic factors that regulate resistance to DNA damage-induced cell death and susceptibility to mutagenesis. Experimental investigations focus on the following areas:
- 1) DNA damage surveillance mechanisms and their linkage to DNA repair, cellular signaling networks and cell cycle checkpoints. Of particular interest is the role of mismatch repair proteins as sensors of DNA damage that consequently activate stress responses.
- 2) Mechanisms of cell death triggered by DNA-targeting anticancer drugs, especially differences in cell death programs between normal and cancer cells and the exploitation of these differences in the optimization of anticancer therapy.
The laboratory explores two classes of DNA-reactive compounds:
- 1) Metal complexes containing chromium (Cr) or platinum (Pt). Hexavalent Cr is a major environmental and occupational carcinogen with widespread human exposure due to its large-scale use in metal alloys and inorganic paints. Pt-based compounds, such as cisplatin and carboplatin, are the most commonly used class of drugs in cancer chemotherapy.
- 2) Agents that cause covalent DNA-protein crosslinks, such as endogenous and exogenous aldehydes, as bifunctional anticancer drugs (platinum-based drugs, mitomycin C and others). The biological role of DNA-protein crosslinks is poorly understood relative to smaller forms of DNA damage but these superbulky lesions are likely to act as potent inducers of large chromosomal rearrangements and cellular senescence (permanent growth arrest).
Principal Investigator: Thomas Bartnikas
The Barnikas laboratory studies the role of metals in human health and disease. While metals are essential for many biological processes, they are toxic when present in excess. Metal deficiency and toxicity can be caused by specific genetic mutations or result from dietary imbalances or environmental exposures.
The laboratory investigates the mechanisms by which metals are acquired by the body, distributed to various tissues and recycled or eliminated once no longer needed. Both mouse models of human disease and tissue culture models are used in the lab. The current focus of the lab is on the regulation of iron metabolism in diseases of iron overload and the interrelationships between metabolism of iron and other metals such as manganese.
Principal Investigator: Suzanne De La Monte
Dr. Suzanne De La Monte leads a research program studying damage to the brain caused by metabolic disease, especially that related to insulin deficiency and insulin resistance. Her work has identified the consequences of chronic alcoholism on the adult brain, and on the effects of alcohol on the developing brain by impairing the movement of cells in the brain as it develops. Work in this laboratory has also shown that insulin resistance may be involved in Alzheimer disease.
Principal Investigator: Weibiao Cao
Dr. Weibiao Cao, in collaboration with Dr. Jack Wands and members of the GI division of Internal Medicine, is investigating the role of activated oxygen species in the pathogenesis of Barrett’s esophagus and the associated increase in incidence of cancer of the esophagus. His findings have shown that the transition from Barrett esophagus to cancer of the esophagus may involve the acid-induced generation of reactive oxygen species. In particular, he has shown that the NADPH oxidase NOX5-S is overexpressed in esophageal cancer cells and that this same pathway mediates hydrogen peroxide production in an acidic environment.