One of the principal goals of diabetes research is to generate a large and renewable supply of human insulin-producing beta cells for replacement therapy. Another is to understand how replacement or replenishment might be accomplished from endogenous, residual beta cells. One attractive and tractable approach is the induction of human beta cell replication, so that mature, differentiated human beta cells derived from endogenous sources, from cadaver pancreatic islets, or from the other sources (such as various types of stem cells or reprogrammed cells), might be expanded to numbers capable of treating large numbers of patients with diabetes. Whereas conventional dogma and widespread experience has suggested that adult human beta cells are terminally differentiated and cannot replicate, the investigators in this application have recently shown that this is not completely true. By manipulating cell cycle control, specifically the G1/S control checkpoint of the cell cycle, this group has shown that: a) human beta cells can be induced to replicate rapidly and still retain their differentiated, functional phenotype: and, b) that many direct and indirect, upstream options for human beta cell cycle activation exist. The goals of this application are to assemble a group of senior scientists who focus on all aspects of human beta cell biology and therapy, to facilitate and expedite human beta cell replication, differentiation and replacement strategies, and to share this expertise with the other members of the Beta Cell Biology Consortium (BCBC).
The Specific Aims are: 1) To Fully Define The Normal Physiology, Mechanisms of Action, Therapeutic Efficacy and Safety of G1/S Cell Cycle Molecules In The Human Beta Cell. 2) To Explore the Regulatory Pathways Upstream Of The G1/S Checkpoint To Define Beta-Cell Specific Pathways To Activate Proliferation in Human Beta Cells. 3) To Share Knowledge, Data, Reagents, Animals, Technologies, and Techniques with Other BCBC Investigators. Data already in hand indicates that there are many novel ways to induce human beta cell replication, and that additional focus and refinement should help transform these approaches from laboratory bench research to human diabetes therapy.

Public Health Relevance

Diabetes affects some 27 million Americans, and results from deficient beta cell numbers and function. The investigative team has developed novel ways to induce robust human beta cell replication using endogenous cell cycle control molecules. The goals of this application are to define precisely how these molecules and their upstream regulators work, which are the best for therapeutic efforts, and how to transfer this knowledge to practical clinical paradigms.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-G (M3))
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Sato, Sheryl M
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Bernal-Mizrachi, Ernesto; Kulkarni, Rohit N; Scott, Donald K et al. (2014) Human ?-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63:819-31
Kang, Li; Dai, Chunhua; Lustig, Mary E et al. (2014) Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice. Diabetes 63:3699-710
Bender, Aaron; Stewart, Andrew F (2014) Good news for the ageing beta cell. Diabetologia 57:265-9
Tessem, Jeffery S; Moss, Larry G; Chao, Lily C et al. (2014) Nkx6.1 regulates islet ?-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proc Natl Acad Sci U S A 111:5242-7
Stewart, Andrew F (2014) Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in ?-cell regeneration research. Diabetes 63:1198-9
Faleo, Gaetano; Berggren, Per-Olof; Pileggi, Antonello (2014) Intravital imaging of cytotoxic T lymphocytes. Methods Mol Biol 1186:121-9
Brissova, Marcela; Aamodt, Kristie; Brahmachary, Priyanka et al. (2014) Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes ? cell regeneration. Cell Metab 19:498-511
Miska, Jason; Abdulreda, Midhat H; Devarajan, Priyadharshini et al. (2014) Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance. J Exp Med 211:441-56
García-Ocaña, Adolfo; Stewart, Andrew F (2014) "RAS"ling ? cells to proliferate for diabetes: why do we need MEN? J Clin Invest 124:3698-700
Reinert, Rachel B; Cai, Qing; Hong, Ji-Young et al. (2014) Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding. Development 141:1480-91

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