Protein Kinase B/Akt in the human islet

人胰岛中的蛋白激酶 B/Akt

基本信息

批准号：
6948172
负责人：
Adolfo Garcia-Ocana
金额：
$ 18.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-15 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6948172
关键词：
Adenoviridae SCID mouse bromodeoxyuridine cell death cell proliferation enzyme activity glucose tolerance test pancreatic islet function pancreatic islet transplantation pancreatic islets polymerase chain reaction serine threonine protein kinase streptozotocin transfection /expression vector xenotransplantation

项目摘要

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

描述（由申请人提供）：最近的临床研究表明，人类胰岛移植有可能替代I型糖尿病患者的胰腺内分泌功能。但是，这些研究还强调了人类胰岛的巨大短缺，这阻碍了在临床实践中使用胰岛移植的大规模使用。为了解决这个问题，一种潜在的方法是开发增加人类胰岛细胞复制，改善人类胰岛细胞功能并增强人类胰岛细胞存活的方法。我们已经表明，肝细胞生长因子（HGF）刺激增殖，增强功能并促进啮齿动物中胰腺β细胞的存活。另外，啮齿动物胰岛中HGF的过表达：（i）减少成功胰岛移植所需的胰岛数量，（ii）显着改善了移植结果。诸如HGF和类似胰岛素样生长因子I的生长因子以及诸如葡萄糖之类的蛋白质激酶B（PKB）/AKT的激活已被证明是重要的细胞内信号传导需求，以增加增殖和防止panceReatic Beta细胞死亡。此外，通过增强β细胞大小，胰岛新生成，β细胞增殖和改善β细胞存活，导致高胰岛素血症和低血糖症。但是，PKB/AKT的本构激活是否对人类胰岛细胞中的这些参数有任何影响。拟议的研究项目的主要目的是确定PKB/AKT的本构激活在增强人类胰岛植入和生存中人类胰岛移植中SCLD小鼠的边缘质量模型中的疗效。我们提出以下具体目标： 1。评估PKB/AKT构型激活在增加人类胰岛细胞增殖，功能和体外生存的功效。 2。评估PKB/AKT的本构激活在改善体内人类胰岛移植结果中人类胰岛移植中SCID小鼠的边缘质量模型中的疗效。这项研究中获得的结果将提供有关人类胰岛中PKB/AKT的构型激活是否会导致人类胰岛细胞的增殖，功能和存活增强，以及小鼠人类胰岛移植的同时改善。如果被翻译成人类，PKB/AKT的构型激活可能是减少成功移植所需的胰岛数量的有吸引力的治疗策略