Recent studies with transgenic and knockout mice have documented the importance of growth factors in the development, growth and function of the pancreatic beta cell in vivo. During the past decade, several studies have shown that hepatocyte growth factor (HGF) is a mitogen for pancreatic beta cells, playing a role in the fetal mesenchyme-induced pancreatic beta cell growth in vitro. Recently, we have shown that transgenic mice over expressing HGF in the pancreatic beta cell, through the use of the rat insulin promoter (RIP), display increased beta cell proliferation, function and survival. While these studies demonstrate the consequences of targeted overexpression of HGF in the beta cell, they do not reveal whether HGF plays a physiological role in the growth, function and survival of the beta cell in adult animals. Our studies have also shown that RIP-HGF transgenic mouse islets markedly improve transplant outcomes in diabetic SCID mice, requiring a lesser amount of islets for successful islet transplantation. Recently, adenoviral-mediated transfer of HGF into normal mouse islets has confirmed the beneficial effects of this islet growth factor in improving islet transplant outcomes in diabetic SCID mice. These studies have suggested that HGF-induced increase in beta cell survival could be an important mechanism implicated in the HGF-induced islet transplant improvement. However, the anti-cell-death effects of HGF in the beta cell, including the mechanisms responsible for such effects, have not been characterized. In addition, our transplant studies have been performed in a situation in which HGF is over expressed in the beta cell. Previous studies have shown that c-met (HGF receptor) mRNA is down regulated in transplanted islet grafts. Studies aimed at over expressing either c-met alone, c-met and HGF, or constitutive active c-met (tpr-met) using the aforementioned adenovirus system could lead to a further improvement in islet transplant outcomes and a greater reduction in the number of islets needed for successful transplantation.
The specific aims of the current proposal are: 1. To further characterize the functional consequences of disrupting HGF receptor (c-met) signaling in the beta cell through the use of RIP-Cre and floxed c-met mice. 2. To further define the mechanisms responsible for HGF-induced survival effects in the beta cell. 3. To determine the effect of c-met overexpression in islet transplant performance. The obtained results should define the physiological role of HGF/c-met in the growth, function, survival and transplant performance of the pancreatic beta cell. ? ?
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