Hepatocyte Growth Factor and the Pancreatic Beta Crell

描述（由申请方提供）：最近对转基因和基因敲除小鼠的研究证明了生长因子在体内胰腺β细胞发育、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细胞的有丝分裂原，在体外胎儿间充质诱导的胰腺β细胞生长中发挥作用。最近，我们已经证明，通过使用大鼠胰岛素启动子（RIP），在胰腺β细胞中过度表达HGF的转基因小鼠显示出β细胞增殖、功能和存活率增加。虽然这些研究证明了β细胞中HGF靶向过表达的后果，但它们没有揭示HGF是否在成年动物中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较少的胰岛。最近，腺病毒介导的肝细胞生长因子转移到正常小鼠胰岛已经证实了这种胰岛生长因子在改善糖尿病SCID小鼠胰岛移植结果中的有益作用。这些研究表明，HGF诱导的β细胞存活率的增加可能是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，包括负责这种作用的机制，尚未被表征。此外，我们的移植研究是在β细胞中HGF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。旨在使用上述腺病毒系统过度表达单独的c-met、c-met和HGF或组成型活性c-met（tpr-met）的研究可以导致胰岛移植结果的进一步改善和成功移植所需的胰岛数量的更大减少。本提案的具体目标是：1.进一步表征通过使用RIP-Cre和floxed c-met小鼠破坏β细胞中HGF受体（c-met）信号传导的功能后果。 2.进一步确定HGF诱导β细胞存活效应的机制。 3.确定c-met过表达对胰岛移植性能的影响。 所获得的结果应定义HGF/c-met在胰腺β细胞的生长、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.