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. The main focus in my laboratory is to study the biology of different hypothalamic neuropeptides involved in the regulation of energy balance and thyroid function.

Biography

Eduardo Nillni, PhD, joined the division of endocrinology 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. He did post-doctoral fellowship research on the membrane biology of parasitic protozoa at Tufts-New England Medical Center in Boston, where he then became a member of the faculty. He subsequently shifted his research to the field of endocrinology and has established a highly productive program investigating neuropeptide biosynthesis, regulation and function, and their relationship to energy balance.

Nillni currently is an executive member of the graduate programs admissions committee of the molecular biology, cell biology and biochemistry (MCB) and the MD-PhD program at Brown University, and he also directs one of the graduate courses in the MCB program. He is a reviewer for several journals, including Endocrinology, and an ad hoc reviewer for the Journal of Biological Chemistry and the Journal of Neurochemistry. Nillni is a member of National Institutes of Health metabolism study section FO6, a reviewer for the Canada Institute of Health, and a member of the Canada Research Chairs Program College of Reviewers.

Among his honors, he was the recipient of the 2001 Bruce Selya Award for Research Excellence at Lifespan, and his work recently 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.

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. The National Science Foundation, for work published in Endocrinology (1996; 137: 5651-5661) and for the NSF Chief Financial Officer's Annual report to Congress in June 1997 that included Dr. Nillni's work.

1999 Master of Arts ad eundem, Board of Fellows, Brown University. Member of the Honorary Alumni at Brown University.

2000 Bruce Selya Award for Research Excellence. It is given by the Lifespan organization that includes most of the Rhode Island hospitals, which are associated with Brown Medical School. This award is given to an outstanding scientist who achieved a reputation for research excellence on the basis of independent scientific work, publications, research funding, and peer recognition.

2005 Monitor for the Hormone Action in Development and Cancer Conference, July 10-15, 2005, Mount Holyoke College, South Hadley, Mass.; chosen by the Board of Directors of the Gordon Research Conferences.

Affiliations

1977 - 1986 Society of Protozoologists
1984 - 1994 American Chemical Society
1987 - 1989 Society of Complex Carbohydrates
1984 - present Federation of American Societies for Experimental Biology (FASEB)
1984 - present The American Society for Cell Biology
1993 - present The Endocrine Society
1995 - present The American Society for the Advance of Science
1996 - present American Neuroendocrine Society
2002 - present Society of General Physiologists

Funded Research

1. 1983-1985 National Institutes of Health (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 Rhode Island 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 (NSF) IBN:94170 PI: E.A. Nillni.
"Processing and targeting of TRH prohormone" Total cost: $700,000

6. 1995 - 1997 NSF Research Experiences for Undergraduates (REUs). PI: E.A. Nillni. Supplement IBN-94170. "Processing and targeting of TRH prohormone"
Total cost: $20,000

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

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

9. 1999 - 2000 NSF REUs. PI: E.A. Nillni. Supplement IBN: 9810349. "Physiological Regulation of proThyrotropin Releasing Hormone Biosynthesis and Processing"
Total cost: $35,000

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

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

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

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

14. 2003 - 2006 National Institute on Drug Abuse (NIDA) 1F31 DA016875-01 E.A. Nillni: Mentor for Lawrence Mulcahy (Brown Graduate Student) pre-doctoral fellowship award.
"Sorting of proTRH peptides"

15. 2004 - 2007 National Institute of Neurological Disorders and Stroke (NINDS) RO1 NS045231 supplement PI: E.A. Nillni "ProTRH sorting to the regulated secretory pathway." This is a two-year supplement award for a total cost of $90,000.00

16. 2005 - 2010 NIH 2 RO1 58148-05 PI: E.A. Nillni. Competitive Renewal
"ProTRH gene transcription and biosynthesis by leptin". Total cost: $1,450.000

Teaching Experience

Protein Processing and Trafficking Bio 228
Eukaryotic Cell Biology Bio 105

Courses Taught

• Protein Processing & Trafficking (Bio228)

View My Full Publication List in pdf format

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)