Our laboratory focuses on the cells that produce insulin, the pancreatic beta-cells. Loss, damage or dysfunction of the beta-cells causes diabetes. Our group explores how beta-cells arise during embryonic development, how they differentiate from the other pancreatic cell types, and what mechanisms control the expression of the genes necessary for these processes and for the function of the mature beta-cells. Ultimately, we believe that this knowledge will help us to understand where these processes break down in diabetes, and will yield novel strategies for curing diabetes.
All of the cells of the mature pancreas develop from a small pool of common progenitor cells in the early gut tube. But how do these unconstrained progenitor cells choose their ultimate cell fate and transform into mature cells? We have approached this problem by asking how these early progenitor cells change the genes that they express, since cellular differentiation can be viewed as a series of alteration in gene expression. Our general strategy has been to identify the molecules that regulate gene expression in progenitors and mature beta-cells. These molecules and their genes are then used as tools to understand the process of beta-cell development by studying both how they regulate gene expression and development and how they are regulated themselves, both in mouse models and in vitro .
In parallel, we apply the accumulating information from these basic studies to the development and testing of methods for producing beta-cells from stem cells for people with diabetes. We believe that the recapitulation of beta-cell genesis in the culture dish, or ultimately even in people, will eventually provide a cure for diabetes.
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Wilson ME, Scheel D, German MS. Gene expression cascades in pancreatic development. Mech Dev. 2003 Jan;120(1):65-80.
Watada, H., Scheel, D., Leung, J., German, M. Distinct gene expression programs function in progenitor and mature islet cells. J Biol Chem 278(19):17130-40 (2003).
Smith, S., Gasa, R., Watada, H., Wang, J., Griffen, S. and German, M. Neurogenin3 and Hepatic Nuclear Factor 1 cooperate in activating pancreatic expression of Pax4. J. Biol. Chem. 278(40):38254-9 (2003).
Gasa, R., Mrejen, C., Leachman, N., Otten, M., Barnes, M., Wang, J., Chakrabarti, S., Mirmira, R., German, M. Pro-endocrine genes coordinate the pancreatic islet differentiation program in vitro PNAS 101(36): 13245-13250 (2004).
Mauvais-Jarvis, F., Smith, S., Le May, C., Leal, S., Gautier, J., Molokhia, M., Riveline, J., Rajan, A., Kevorkian, J., Zhang, S., Vexiau, P., German, M., Vaisse, C., PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics 13(24):3151-9 (2004) .
information last updated June 2005
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Biomedical Sciences (BMS) Graduate Program
