The mission of the Beta Cell Biology Consortium (BCBC) is to generate functional human glucose-responsive, insulin-producing (-cells and to promote (-cell regeneration or proliferation of existing (-cells. While current research has identified many transcription factors and inductive signals that promote critical steps in mouse islet development, and that knowledge is guiding efforts to generate human beta cells from stem and progenitor cells, we have also learned that mouse and human islets differ significantly in terms of cellular composition, function, replication, regenerative capacity, and gene expression. These distinctive features of human islets and the need to translate emerging findings from rodent islet biology to human islets serve as the basis of our proposal. Our broad-based, interdisciplinary scientific team, consisting of experts in pancreatic islet and stem cell biology, islet regeneration, developmental biology, and """"""""humanized"""""""" mice, will test the overall hypothesis that key genes and/or environmental stimuli which promote rodent (-cell proliferation can similarly induce the proliferation or regeneration of human or non-human primate (NHP) (-cells. We propose three specific aims: 1) Determine if signals that induce mouse (-cell proliferation also induce human and NHP (-cell proliferation in vivo and evaluate the effect of local inflammation on human and NHP (-cell proliferation. 2) Define the gene expression profile of proliferating human and NHP (-cells and build on these findings to induce proliferation of adult human (-cells. 3) Identify and characterize the regulators allowing and limiting postnatal islet (-cell proliferation in rodents, NHPs, and humans. Importantly, our investigative team will enhance the BCBC's team science-based efforts by: 1) focusing on human islet biology to complement and synergize with investigators working on either mouse pancreas and islet biology and/or human ES or iPS cells;2) adding considerable expertise in the molecular mechanisms underlying (-cell development, cell fate determination, and proliferation;and 3) bringing and developing valuable research tools and technologies such as """"""""humanized"""""""" mouse models, in vitro and in vivo models to study the proliferation and regeneration of fetal, juvenile, and adult human and NHP islets, and unique mouse models of (-cell proliferation and regeneration.

Public Health Relevance

In both type 1 and type 2 diabetes, there are an insufficient number of insulin-producing cells. This interdisciplinary team is working to develop approaches to stimulate human insulin-producing cells to proliferate and regenerate as a new therapy for diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089572-02
Application #
8142740
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M3))
Program Officer
Sato, Sheryl M
Project Start
2010-09-10
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$2,089,419
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Cogger, Kathryn F; Sinha, Ankit; Sarangi, Farida et al. (2017) Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. Nat Commun 8:331
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
Chakravarthy, Harini; Gu, Xueying; Enge, Martin et al. (2017) Converting Adult Pancreatic Islet ? Cells into ? Cells by Targeting Both Dnmt1 and Arx. Cell Metab 25:622-634
Dai, Chunhua; Hang, Yan; Shostak, Alena et al. (2017) Age-dependent human ? cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J Clin Invest 127:3835-3844
Matsuoka, Taka-Aki; Kawashima, Satoshi; Miyatsuka, Takeshi et al. (2017) Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet ?-Cells Into ?-Cells In Vivo. Diabetes 66:1293-1300
Westacott, Matthew J; Farnsworth, Nikki L; St Clair, Joshua R et al. (2017) Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets. Diabetes 66:2436-2445
Aamodt, Kristie I; Powers, Alvin C (2017) Signals in the pancreatic islet microenvironment influence ?-cell proliferation. Diabetes Obes Metab 19 Suppl 1:124-136
Banerjee, Ronadip R; Cyphert, Holly A; Walker, Emily M et al. (2016) Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet ?-Cells. Diabetes 65:2331-41
Babon, Jenny Aurielle B; DeNicola, Megan E; Blodgett, David M et al. (2016) Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 22:1482-1487
Ceddia, Ryan P; Lee, DaeKee; Maulis, Matthew F et al. (2016) The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice. Endocrinology 157:220-32

Showing the most recent 10 out of 85 publications