Fred Levine's Research Focus
Diabetes is a disease in which there is an insufficient amount of insulin, produced by the pancreatic b-cells, to control the blood glucose concentration. In type I diabetes, the b-cell are destroyed by an autoimmune response, while in type II diabetes, the b-cells are dysfunctional and are ultimately lost because of obesity-associated pathology. Our laboratory is interested in how b-cells regenerate under normal and pathophysiological conditions, with the goal of developing new therapies for diabetes that result in an increased number of those cells. Our studies of b-cell growth have also led us to develop lead compounds that are active in cancer, an interesting connection as both obesity and diabetes are now recognized as major risk factors for cancer.
Fred Levine's Research Report
The major interest in the laboratory is pancreatic beta-cell biology and specifically the control of beta-cell growth and differentiation in the adult pancreas. In both type I and type II diabetes, β-cell mass decreases and is a major factor in the pathogenesis of diabetes. Thus, one major question in which we are interested is the existence and nature of adult endocrine stem/progenitor cells. Using both human and rodent models, we study cells in vitro and in vivo to determine the competence of various cell populations to undergo endocrine differentiation in response to defined stimuli. The goal is to achieve a sufficient understanding of the process of adult β-cell regeneration to allow us to enhance β-cell mass in diabetes.
A second major area of emphasis is to use high-throughput screening to discover compounds that modulate important aspects of β-cell biology. Our focus has been on modulation of insulin promoter activity, as that gene is acted upon by many diabetogenic stimuli. We have isolated and are characterizing a number of compounds and genes that were discovered in the screening process. Recently, we have discovered ligands for the orphan nuclear receptor HNF4a. HNF4a is involved in a number of disease processes, including diabetes, liver disease, and cancer.
Fred Levine's Bio
Dr. Levine is Emeritus Professor at Sanford Burnham Prebys. Prior to that, he was a Professor in the Department of Pediatrics at the University of California, San Diego School of Medicine, where he continues to see children with inherited metabolic diseases. Dr. Levine received his undergraduate degree in biochemistry from Harvard and his M.D. and Ph.D. degree in genetics from the University of Washington. His clinical training as a pediatric geneticist was at the Children’s Hospital of Philadelphia. Dr. Levine has been working in the field of cell transplantation therapies for diabetes and b-cell biology for more than fifteen years. His laboratory was the first to develop immortalized cell lines from the human endocrine pancreas as models of beta-cell growth and differentiation. He has made insights into cellular senescence in the endocrine pancreas, finding that b-cells undergo rapid senescence when stimulated to proliferate. Most recently, he and his co-workers demonstrated the existence of endocrine stem cells in the adult human pancreas. The laboratory continues to pursue the development of cell therapies for diabetes using a variety of approaches, including high throughput screening.
Education
1979-86: Ph.D., University of Washington (Genetics)
1979-86: M.D., University of Washington
1975-79: A.B., Harvard University (Biochemistry)
Postgraduate Training
1989-91: Genetics Fellow, Dept. of Pediatrics, UCSD School of Medicine
1988-89: Clinical Genetics Fellow, Children's Hosp. of Philadelphia
1987-89: Pediatric Resident, Children's Hosp. of Philadelphia
1986-87: Pediatric Intern, Children's Hosp. of Philadelphia
Other Appointments
Health Sciences Clinical Professor of Pediatrics, UCSD School of Medicine
Attending Physician, Rady Children's Hospital
Publications
HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.
Kiselyuk A, Lee SH, Farber-Katz S, Zhang M, Athavankar S, Cohen T, Pinkerton AB, Ye M, Bushway P, Richardson AD, Hostetler HA, Rodriguez-Lee M, Huang L, Spangler B, Smith L, Higginbotham J, Cashman J, Freeze H, Itkin-Ansari P, Dawson MI, Schroeder F, Cang Y, Mercola M, Levine F
Chem Biol 2012 Jul 27 ;19(7):806-18
Induction of β-cell replication by a synthetic HNF4α antagonist.
Lee SH, Piran R, Keinan E, Pinkerton A, Levine F
Stem Cells 2013 Nov ;31(11):2396-407
Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells.
Lee SH, Hao E, Levine F, Itkin-Ansari P
Islets 2011 Nov-Dec ;3(6):358-66
Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries.
Reches G, Blondheim Shraga NR, Carrette F, Malka A, Saleev N, Gubbay Y, Ertracht O, Haviv I, Bradley LM, Levine F, Piran R
Inflamm Regen 2022 Nov 29 ;42(1):52
Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation.
Lee SH, Hao E, Scharp D, Levine F
Islets 2018 May 3 ;10(6):1-12
High-throughput screening and bioinformatic analysis to ascertain compounds that prevent saturated fatty acid-induced β-cell apoptosis.
Lee SH, Cunha D, Piermarocchi C, Paternostro G, Pinkerton A, Ladriere L, Marchetti P, Eizirik DL, Cnop M, Levine F
Biochem Pharmacol 2017 Aug 15 ;138:140-149
PAR2 regulates regeneration, transdifferentiation, and death.
Piran R, Lee SH, Kuss P, Hao E, Newlin R, Millán JL, Levine F
Cell Death Dis 2016 Nov 3 ;7(11):e2452
Maternal embryonic leucine zipper kinase regulates pancreatic ductal, but not β-cell, regeneration.
Chung CH, Miller A, Panopoulos A, Hao E, Margolis R, Terskikh A, Levine F
Physiol Rep 2014 Sep 1 ;2(9)
Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes.
Piran R, Lee SH, Li CR, Charbono A, Bradley LM, Levine F
Cell Death Dis 2014 Jul 31 ;5(7):e1357
