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.
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.
|Dean, E Danielle; Li, Mingyu; Prasad, Nripesh et al. (2017) Interrupted Glucagon Signaling Reveals Hepatic ? Cell Axis and Role for L-Glutamine in ? Cell Proliferation. Cell Metab 25:1362-1373.e5|
|Hayes, Heather L; Zhang, Lu; Becker, Thomas C et al. (2016) A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation. Mol Cell Biol 36:2918-2930|
|Damond, Nicolas; Thorel, Fabrizio; Moyers, Julie S et al. (2016) Blockade of glucagon signaling prevents or reverses diabetes onset only if residual ?-cells persist. Elife 5:|
|Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of ?-cells and type 1 diabetes. J Autoimmun 71:59-68|
|Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70|
|Conrad, Elizabeth; Dai, Chunhua; Spaeth, Jason et al. (2016) The MAFB transcription factor impacts islet ?-cell function in rodents and represents a unique signature of primate islet ?-cells. Am J Physiol Endocrinol Metab 310:E91-E102|
|Stewart, Andrew F; Hussain, Mehboob A; García-Ocaña, Adolfo et al. (2015) Human ?-cell proliferation and intracellular signaling: part 3. Diabetes 64:1872-85|
|Chen, Hainan; Kleinberger, Jeffrey W; Takane, Karen K et al. (2015) Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human ?-Cells. Diabetes 64:3784-97|
|Fotino, Carmen; Vergani, Andrea; Fiorina, Paolo et al. (2015) P2X receptors and diabetes. Curr Med Chem 22:891-901|
|Wang, Peng; Alvarez-Perez, Juan-Carlos; Felsenfeld, Dan P et al. (2015) A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 21:383-8|
Showing the most recent 10 out of 49 publications