Protein Kinase B/Akt in the human islet

描述(由申请人提供)： 最近的临床研究证明，人胰岛移植有可能取代I型糖尿病患者的胰腺内分泌功能。然而，这些研究也强调了人类胰岛的巨大短缺，这阻碍了胰岛移植在更大规模的临床实践中的使用。为了解决这一问题，一个潜在的途径是开发方法来增加人胰岛细胞的复制，改善人胰岛细胞的功能，提高人胰岛细胞的存活率。我们已经证明，肝细胞生长因子(HGF)可以刺激啮齿类动物的胰岛β细胞的增殖，增强其功能并促进其存活。此外，HGF在啮齿动物胰岛中的过表达：(I)减少了成功移植胰岛所需的胰岛数量，(Ii)显著改善了移植结果。HGF、胰岛素样生长因子-I等生长因子和葡萄糖等营养物质激活蛋白激酶B(PKB)/Akt是促进啮齿动物胰岛细胞增殖和防止胰岛β细胞死亡的重要细胞内信号转导途径。此外，在转基因小鼠中，通过增加β细胞大小、胰岛新生、β细胞增殖和改善β细胞存活而显著增加β细胞质量，从而导致高胰岛素血症和低血糖。然而，在人类胰岛细胞中，PKB/Akt的结构性激活是否对这些参数有任何影响是完全未知的。该研究项目的主要目的是确定在SCLD小鼠的人胰岛移植边缘质量模型中，PKB/Akt的结构性激活在增强人胰岛植入和存活方面的有效性。我们提出了以下具体目标： 1.评价PKB/Akt结构性激活对体外培养的人胰岛细胞增殖、功能和存活的影响。 2.在SCID小鼠边缘质量人胰岛移植模型中，评价PKB/Akt的结构性激活对改善体内人胰岛移植结果的有效性。 本研究的结果将为人胰岛PKB/Akt的结构性激活是否会导致人胰岛细胞的增殖、功能和存活的增强以及人胰岛在小鼠体内移植的改善提供信息。如果将PKB/Akt翻译到人类身上，可能是一种有吸引力的治疗策略，可以减少成功移植所需的胰岛数量

DESCRIPTION (provided by applicant): Recent clinical studies have documented that human islet transplantation has the potential to replace pancreatic endocrine function in patients with Type I diabetes. However, these studies have also highlighted an enormous shortage of human islets that impedes the use of islet transplantation in clinical practice on a larger scale. To solve this problem, one potential approach is to develop methods to increase human islet cell replication, to improve human islet cell function and to enhance human islet cell survival. We have shown that hepatocyte growth factor (HGF) stimulates proliferation, enhances function and promote survival of the pancreatic beta cell in rodents. In addition, overexpression of HGF in rodent islets: (i) reduces the number of islets required for successful islet transplantation, and (ii) markedly improves transplant outcomes. Activation of Protein-Kinase B (PKB)/Akt by growth factors such as HGF and insulin-like growth factor-I, and nutrients such as glucose, has been shown to be an important intracellular signaling requirement for increasing proliferation and preventing pancreatic beta cell death in rodents. Moreover, beta cell-specific expression of a constitutively active form of PKB/Akt in transgenic mice markedly increases beta cell mass, by enhancing beta cell size, islet neogenesis, beta cell proliferation and improving beta cell survival, resulting in hyperinsulinemia and hypoglycemia. However, whether constitutive activation of PKB/Akt has any impact on these parameters in human islet cells is completely unknown. The primary goal of the proposed research project is to determine the efficacy of constitutive activation of PKB/Akt in enhancing human islet engraftment and survival in a marginal mass model of human islet transplantation in SClD mice. We propose the following Specific Aims: 1. To evaluate the efficacy of constitutive activation of PKB/Akt in increasing human islet cell proliferation, function and survival in vitro. 2. To assess the efficacy of constitutive activation of PKB/Akt in improving in vivo human islet transplant outcomes in a marginal mass model of human islet transplantation in SCID mice. The results obtained in this study will provide information on whether constitutive activation of PKB/Akt in human islets will result in enhanced proliferation, function and survival of human islet cells and a concomitant improvement in human islet transplantation in mice. If translated into humans, constitutive activation of PKB/Akt might be an attractive therapeutic strategy for reducing the number of islets required for successful transplantation