The development of genetically engineered mouse models for research into the function of proteins relevant for diseases has risen considerably over the last decade. These models are particularly useful for the translation of basic knowledge biomedical to prevention or new treatments for human disease and provide invaluable insights into the cause and biology of diseases. Thus, in accordance with the R21 program announcement (PA-07-336) """"""""Development of animal models and related biological models for research"""""""" the objective of this exploratory application is to characterize a mouse model deficient for p53 protein specifically in beta cells to directly examine its role in function, growth and survival of insulin-producing 2-cells. Further, as required by the program announcement, the mouse model will be relevant to two different institutes - NIDDK and NCI - and most importantly, the model will be made available to the research community in accordance with the federal shared organism requirements. The investigator has a long-standing interest in growth factor signaling pathways in islet cells that is relevant to type 2 diabetes (NIDDK). The studies will be performed in consultation with D. Hanahan PhD (UCSF), a leader in the pancreatic cancer field (NCI). Thus, this application meets all the important requirements of the PA. The mechanisms and proteins relevant for 2-cell growth and regeneration are only slowly being unraveled. Since in vivo studies in humans to examine 2-cell growth are virtually impossible most studies are based on cultured human islets and obviously do not provide true insights in the pathways regulating 2-cell growth. Therefore, many investigators including our laboratory have used mice as models to examine the proteins and pathways that mediate 2-cell growth and apoptosis. While this proposal is high risk because there may be no major phenotype in the mutant mice, we believe this is unlikely based on our preliminary data. On the contrary, it is highly likely the studies will yield crucial clues to the pathways that are relevant for 2-cell growth and mitosis.
The Specific Aims i nclude: Phenotypic characterization of inducible 2-cell-specific p53 knockout mice (i-2p53KO);test the hypothesis that inducible knockout of p53 in 2-cells leads to 2-cell proliferation and potential tumor formation;Test the hypothesis that high fat feeding prevents compensatory 2-cell growth response in i-2p53KO mice;Dissect the mechanisms and identify proteins that link growth factor signaling pathways with p53 using primary islets derived from i-2p53KO mice.

Public Health Relevance

The studies outlined in this proposal address an important problem in islet biology - understanding the pathways and proteins that underlie the growth and proliferation of insulin-secreting beta-cells. Using unique genetically engineered mouse models and cell biological techniques we will identify the proteins that are critical for understanding the pathways that are critical for the control of mass of insulin-producing beta-cells. The proposed studies are aimed at the long-term goal of developing therapeutic strategies to prevent or delay the development of cancer and diabetes.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory/Developmental Grants (R21)
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Molecular and Cellular Endocrinology Study Section (MCE)
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O'Neill, Raymond R
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Joslin Diabetes Center
United States
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Kulkarni, Rohit N; Mizrachi, Ernesto-Bernal; Ocana, Adolfo Garcia et al. (2012) Human β-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes 61:2205-13
Hinault, Charlotte; Kawamori, Dan; Liew, Chong Wee et al. (2011) Δ40 Isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. Diabetes 60:1210-22