Protein Kinase B/Akt in the human islet

人胰岛中的蛋白激酶 B/Akt

• 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
• 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

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应用。为了解决这个问题，一种潜在的方法是开发增加人胰岛细胞复制、改善人胰岛细胞功能和提高人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，促进啮齿动物胰腺β细胞的存活。此外，HGF在啮齿动物胰岛中的过表达：（i）减少成功胰岛移植所需的胰岛数量，和（ii）显著改善移植结果。蛋白激酶B（PK B）/Akt被生长因子如HGF和胰岛素样生长因子-I以及营养物如葡萄糖激活，已显示是啮齿动物中增加增殖和防止胰腺β细胞死亡的重要细胞内信号传导要求。此外，转基因小鼠中组成型活性形式PKB/Akt的β细胞特异性表达通过增强β细胞大小、胰岛新生、β细胞增殖和改善β细胞存活来显着增加β细胞质量，从而导致高胰岛素血症和低血糖。然而，PKB/Akt的组成性激活是否对人胰岛细胞中的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PKB/Akt的组成性激活在SClD小鼠中人胰岛移植的边缘质量模型中增强人胰岛植入和存活的功效。我们提出以下具体目标： 1.目的探讨组成性激活PKB/Akt对体外培养的人胰岛细胞增殖、功能和存活的影响。 2.评估PKB/Akt组成性激活在改善SCID小鼠人胰岛移植边缘质量模型中体内人胰岛移植结局方面的疗效。 本研究中获得的结果将提供关于人胰岛中PKB/Akt的组成性激活是否会导致人胰岛细胞的增殖、功能和存活增强以及小鼠中人胰岛移植的伴随改善的信息。如果将PKB/Akt的组成性激活转化为人类，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