Hepatocyte Growth Factor and the Pancreatic Beta Cell

描述（由申请人提供）：最近对转基因和基因敲除小鼠的研究已经证明了生长因子在体内胰腺β细胞的发育、生长和功能中的重要性。在过去的十年中，一些研究表明肝细胞生长因子（HGF）是胰腺β细胞的丝裂原，在胎儿间充质诱导的胰腺β细胞体外生长中发挥作用。最近，我们已经证明转基因小鼠在胰腺β细胞中过表达HGF，通过使用大鼠胰岛素启动子（RIP），显示β细胞增殖，功能和存活增加。虽然这些研究证明了HGF在β细胞中靶向过表达的后果，但它们并没有揭示HGF是否在成年动物β细胞的生长、功能和存活中起生理作用。我们的研究还表明，RIP-HGF转基因小鼠胰岛显著改善了糖尿病SCID小鼠的移植结果，成功的胰岛移植需要更少的胰岛。最近，腺病毒介导的HGF转移到正常小鼠胰岛，证实了这种胰岛生长因子在改善糖尿病SCID小鼠胰岛移植结果方面的有益作用。这些研究表明，hgf诱导的β细胞存活增加可能是hgf诱导的胰岛移植改善的重要机制。然而，HGF在β细胞中的抗细胞死亡作用，包括这种作用的机制，尚未被表征。此外，我们的移植研究是在HGF在β细胞中过度表达的情况下进行的。先前的研究表明，c-met （HGF受体）mRNA在移植的胰岛移植物中下调。针对单独表达c-met、c-met和HGF，或使用上述腺病毒系统过表达组成型活性c-met （tpr-met）的研究，可能会进一步改善胰岛移植结果，并进一步减少成功移植所需的胰岛数量。当前提案的具体目标是：1。通过使用RIP-Cre和固定的c-met小鼠，进一步表征破坏β细胞中HGF受体（c-met）信号的功能后果。2. 进一步明确hgf诱导β细胞存活效应的机制。3. 目的：探讨c-met过表达对胰岛移植性能的影响。所得结果应明确HGF/c-met在胰腺β细胞生长、功能、存活和移植性能中的生理作用。

DESCRIPTION (provided by applicant): 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.