The overall goal of this proposal is to identify means for improving ?-cell regeneration in the adult pancreas. With previous BCBC funding we have developed a transgenic model of inducible total or partial ?-cell ablation (RIP-DTR). In these mice, ?-cell regeneration occurs after near total ?-cell loss, and this relies on the transdifferentiation of adult mature ?-cells to ?-cells. In this proposal we will test, among different aspects, i) whether ?-cell regeneration in RIP-DTR mice can be enhanced by promoting the observed spontaneous ?-to-?-cell conversion. ?-cell regeneration occurs by ?-cell replication in other diabetes models of less severe ?-cell ablation. Regeneration in RIP-DTR mice is less efficient than in these mouse models probably because DT treatment leaves almost no ?-cells (DT stands for diphtheria toxin, the agent used to induce ?-cell ablation in these mice). Accordingly, ?-cell repopulation principally occurs in RIP-DTR mice by a mechanism of ?-cell reprogramming. One of our objectives will be ii) to determine if age plays a role in ?-cell regeneration / ?-cell reprogramming , since proliferation in islets has been shown to profoundly decline in older rodents and humans. In addition, we will examine the molecular mechanisms controlling ?- to ?-cell transdifferentiation in RIP-DTR mice. These analyses will be performed in parallel with studies aimed at iii) exploring whether cell fate reprogramming is a common feature of different adult pancreatic cell types, and is not restricted to ? - cells only. The heterologous origin of new ?-cells is particularly interesting, since the almost complete ?-cell depletion achieved in RIP-DTR mice recreates a condition very similar to the situation found in Type 1 diabetic patients.

Public Health Relevance

Understanding the mechanisms of ?-cell regeneration and identifying the cells and factor(s) that enhance the formation and/or growth and/or survival of ?-cells should have a high impact on the development of new treatments for human T1D.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089566-05
Application #
8717651
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
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$100,000
Indirect Cost
$7,400
Name
University of Geneva
Department
Type
DUNS #
481076537
City
Geneva
State
Country
Switzerland
Zip Code
CH-12-11
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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
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