Faculty Profile: Eduardo A. Nillni, PHD, MS

Eduardo A. Nillni
Eduardo A. Nillni, PHD, MS
Professor of Medicine
Molecular Biology, Cell Biology & Biochemistry
Work: +1 401-444-5733
Obesity and its medical complications including type 2 diabetes, cardiovascular disease, dyslipidemia, and cancer account for more than 300,000 deaths per year in the United States. Obesity occurs as a result of a longstanding imbalance between energy intake and energy expenditure. A better understanding of the mechanisms underlying the pathogenesis of obesity is essential for the development of effective therapies. My laboratory study the biology of different hypothalamic neuropeptide hormones affected by endoplasmic reticulum stress during diet-induced obesity, and nutrient sensors involved in the regulation of energy balance.

Biography

Dr. Eduardo A. Nillni joined the Division of Endocrinology in the Department of Medicine as a member of the research faculty in 1989. His education included a master's degree in Biological Sciences from the University of Buenos Aires, Argentina, and a PhD from the Hadassah Medical School, Hebrew University of Jerusalem, Israel, where he studied the Biochemistry of Parasitic Protozoa. Dr. Nillni did his post-doctoral fellowship in membrane biology of parasitic protozoa at Tufts-New England Medical Center in Boston, and he then became a member of the faculty in 1984. He subsequently shifted his research to the field of Endocrinology and has established a highly productive program studying the role of neuropeptide hormones, nutrient sensors in the hypothalamus and the adiposite hormone leptin involved in the regulation of food intake energy homeostasis.

Dr. Nillni currently is an appointed member of the Integrative Physiology of Obesity and Diabetes National Institutes of Health Study Section (IPOD), a member of the Editorial Board of Endocrinology, and in 2010 he will be the Chairman of the Lifespan affiliated Hospitals Institutional Animal Care and Use Committee. Dr. Nillni is also a NIH Trainer in the Molecular Biology, Cell Biology & Biochemistry, and Pathobiology graduate programs. He is also an ad hoc reviewer for several journals, including the Journal of Biological Chemistry and the Journal of Neurochemistry, American Journal of Physiology among many. Among his honors, he was the recipient of the 2001 Bruce Selya Award for Research Excellence at Lifespan, and his work was featured in a National Science Foundation progress report to the U.S. Congress.

Institutions

RIH

Research Description

Cell Biology Program

Nillni's laboratory has made substantial contributions in studies related to the neurobiology of proThyrotropin Releasing Hormone (proTRH), a precursor protein to TRH (pyroGlu-His-ProNH2). The biosynthesis of TRH and other proTRH-derived peptides follows a protein processing mechanism, which is similar to those described for other secretory peptides. It begins with a mRNA-directed ribosomal translation followed by a post-translational limited proteolysis of the larger precursor, proTRH. This process occurs while proTRH is being transported from the trans Golgi network to newly formed immature secretory granules and beyond. These granules then mature and are targeted to their specific sites of secretion at the plasma membrane of the cell. His laboratory also demonstrated that cleavage of proTRH to generate biologically active TRH occurs at the paired basic residues by the action of two members of the family of prohormone convertases 1/3 and 2 (PC1/3 and PC2), followed by the action of carboxypeptidase E and D. Recently his laboratory has identified a prodomain present in the amino terminal side of proTRH that could be involved in the proper folding and/or aggregation of proTRH for its proper sorting to the regulated secretory pathway. Another important prohormone studied in Nillni's laboratory is prooipiomelanocortin (POMC). His laboratory is actively investigating the processing and sorting of this polypeptide in two brain areas the arcuate nucleus and the brain Stem, which are important sites involved in energy balance regulation.

Obesity Program

Severe obesity is associated with dramatic changes in body fat content, particularly subcutaneous or intra-abdominal (visceral) fat that results in cardiovascular disease and type 2 diabetes. Obesity has reached epidemic proportions worldwide and affects 1 in 3 Americans. A better understanding of the causes of obesity to further develop new anti-obesity drugs lies in uncovering the molecular and physiologic mechanisms that regulate appetite, satiety, and energy balance. Dr. nillni's work in this area provided the first direct evidence for leptin-mediated regulation of preproTRH mRNA expression as well as TRH prohormone processing and secretion. He demonstrated that PC1/3 and PC2 enzymes involved in prohormone processing, are key in the maturation of several anorexogenic hypothalamic peptides important in calorie expenditure, which are regulated by leptin. His laboratory also has defined novel proTRH-derived peptides with potential biologic function(s).

Energy expenditure is a pivotal mechanism for maintaining body weight. The hormone leptin, produced principally in adipose tissue, is a key physiologic regulator in providing information on energy stores and energy balance to brain centers that regulate appetite, energy expenditure and neuroendocrine function. One of the major energy expenditure mechanisms is through the action of leptin on TRH and POMC neurons, which produces the peptide MSH. These two anorexigenic peptides are key regulators in maintaining energy balance. Therefore, the main focus in Nillni's laboratory is to study the biology of different neuropeptides involved in the regulation of energy balance, thyroid function, and thermogenesis.

Grants and Awards

1973 - 1975 Research Student Scholarship. The National Institute of Pharmacology. Buenos Aires, Argentina.
1978 - 1978 Research Student Scholarship. The Hebrew University of Jerusalem, Jerusalem, Israel.
1996 Distinguished Scientist Recognition from the National Science Foundation from the work published in Endocrinology (vol 137, 5651-5661, 1996) and by the NSF Chief Financial Officer's Annual report that included Dr. Nillni's work to Congress in June 1997.
1999 The Board of Fellows at Brown University awarded the Master of Arts ad eundem. Member of the Honorary Alumni at Brown University.
2000 Bruce Selya Award for Research Excellence. This award is given on the basis of independent scientific work, publications, research funding, and peer recognition.

Affiliations

REVIEWER FOR THE FOLLOWING SCIENTIFIC JOURNALS

2004 - present Member of the Editorial Board of Endocrinology
1998 - present Ad hoc reviewer for the Journal of Neurochemistry
1999 - present Ad hoc reviewer for the Journal of Biological chemistry
2005 - present Ad hoc reviewer for the Journal of Clinical Endocrinology and Metabolism.
2006 - present Ad hoc reviewer for Molecular and cellular Endocrinology
2009 - present Ad hoc reviewer for Journal of Clinical Investigation
2011 - present Ad hoc reviewer for Nature
2012 - present Ad hoc reviewer for Cell Metabolism
2010 - present Ad hoc reviewer for American Journal of Physiology

MEMBERSHIP IN SOCIETIES

1984 - 1994 American Chemical Society
1977 - 1986 Society of Protozoologists
1993 - present The Endocrine Society
1984 - 2007 The American Society for Cell Biology
1995 - present The American Society for the Advance of Science
1984 - present FASEB
1987 - 1989 Society of Complex Carbohydrates
1996 – 2003 American Neuroendocrine Society
2009 - 2011 American Thyroid Asociation

Funded Research

GRANTS

1. 1983-1985 NIH RO1 AI20263 co-PI: E.A. Nillni "Synthesis and membrane insertion of plasmodial proteins". Total cost: $1.200,000

2. 1986 Charlton Fund : PI: E.A. Nillni. "Export of parasites-synthesized proteins through the vacuole membrane of Plasmodiuknowlesi". Total cost: $20,000

3. 1988-1990 NIH DK34540: co-PI E.A. Nillni. "Secretion of TRH and other neural peptides". Total cost: $800,000

4. 1991- 1992 RI Foundation PI: E.A. Nillni. "Determination of the intracellular ProTRH processing in the transfected AtT20 cell line". Total cost: $5,000

5. 1995 - 1998 National Science Foundation IBN:94170 PI: EA Nillni. "Processing and targeting of TRH prohormone" Total cost: $700,000

6. 1995 - 1997 National Science Foundation REUs . PI: EA Nillni. Supplement IBN-94170. Total cost: $20,000

7. 1997 - 2002 NIH1RO1DA10521-01A1 Subcontract: EA Nillni "Role of proTRH-derived peptides in the periaquaductal gray during opiate withdrawal". Total cost: $80,000

8. 1998 - 2001 National Science Foundation IBN: 9810349. PI: EA Nillni. Competitive Renewal. "Physiological Regulation of proThyrotropin Releasing Hormone Biosynthesis and Processing". Total cost: $730,000

9. 1999 - 2000 National Science Foundation REUs . PI: EA Nillni. Supplement
IBN: 9810349. Total cost: $35,000

10. 1997 - 2003 NIH 1RO1 DA 10762-01 Sub-contract: EA Nillni. "The role of preproTRH-derived peptides in cocaine action". Total cost: $75,000

11. 2000 - 2004 NIH 1RO1 58148-01 PI: EA Nillni. "ProTRH gene transcription and biosynthesis by leptin". Total cost: $1,700.000

12. 2002 - 2007 NIH 1RO1. CoPI, Sub-contract: EA Nillni. "Regulation of hypothalamic POMC by leptin". Total cost: $430,000

13. 2003 - 2007 NIH RO1 NS045231-1 PI: EA Nillni
"ProTRH sorting to the regulated secretory pathway" Total cost: $1,340,000

14. 2003 - 2006 NIDA 1F31 DA016875-01 EA Nillni: Mentor for Lawrence Mulcahy (Brown Graduate Student) pre-doctoral fellowship award. "Sorting of proTRH peptides"

15. 2004 - 2007 NINDS RO1 NS045231 supplement PI: EA Nillni
This is a two-year supplement award for a total cost of $90,000.00

16. 2005 - 2009 NIH 2 RO1 58148-05 PI: EA Nillni. Competitive Renewal
"ProTRH gene transcription and biosynthesis by leptin". Total cost:
$1,450.000

17. 2009 - 2010 NIH 2R56DK058148-09 PI: EA Nillni
"ProTRH gene transcription and biosynthesis by leptin"
Total cost: $180,000

18. 2010 - 2014 NIH R01 DK085916-01 PI: EA Nillni
"Hypothalamic SIRT1 and Energy Balance. Goal of this project is to study the role of SIRT1 in energy balance and appetite.
Total cost: $1,700,000

19. 2012 - 2014 NIH 3R01 DK085916-03S1 PI: EA Nillni
Hypothalamic SIRT1 and Energy Balance. Goal of this project is to determine the role of hypothalamic Sirt1 in the diet-induced obesity (DIO) condition. Total cost: $ $82,528

PENDING GRANTS

1R01 DK095488-01A1 EA Nillni (PI) 12/1/12- 11/30/2017
NIH/NIDDK $1,900,000.00
Obesity, Hypothalamic Stress and Melanocortin Peptides

1R01DK099279-01 EA Nillni (PI) 07/01/2013-6/30/2018
$1,900,000.00
Cellular Mechanisms Regulating the Anorexigenic Pro-Opiomelanocortin (POMC) in Diet-Induced Obesity

1 R01 HD076246-01 EA Nillni (sub PI) 4/1/2013-3/31/2018
PCOS Neuroendocrine dysfunction $118,575.00

Teaching Experience

Protein Processing and Trafficking Bio 228
Eukaryotic Cell Biology Bio 105

Courses Taught

  • Protein Processing & Trafficking (Bio228)

Selected Publications

  • Perello M, Stuart RC, Nillni EA. The role of intracerebroventricular administration of leptin in the stimulation of prothyrotropin releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology. 2006 Jul;147(7):3296-306 (2006)
  • Mulcahy LR, Vaslet CA and Nillni EA. 2005. Prohormone-Convertase 1 Processing Enhances Post-Golgi Sorting of proThyrotropin Releasing Hormone-Derived Peptides. J Biol Chem. 2;280(48):39818-26 (2005)
  • Guo L, Münzberg H, Stuart RC, Nillni EA, and Bjørbæk C. 2004. N-acetylation of hypothalamic alpha-melanocyte-stimulating hormone and regulation by leptin. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11797-802. (2004)
  • Sanchez VC, Goldstein J, Stuart RC, Hovanesian V, Huo L, Munzberg H, Friedman TC, Bjorbaek C and Nillni EA. 2004. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J Clin Invest. 2004 Aug; 114(3): 357-69. (2004)