Protein Kinase C (PKC) Zeta and the Pancreatic Beta Cell

描述（由申请人提供）：糖尿病是由功能性β细胞缺乏引起的。旨在分析关键生长因子/激素和细胞内信号分子如何增加β细胞增殖，防止β细胞损失和促进胰岛素释放的研究对于未来糖尿病的治疗方法至关重要。在本研究中，我们重点研究了磷脂酰肌醇3'-激酶的一个重要下游靶点，即非典型蛋白激酶C （PKC）信号通路。该通路的激活增强了许多细胞类型的增殖、功能和存活。重要的是，在β细胞中，我们已经证明了生长因子和营养物质（如葡萄糖）可以激活非典型异构体PKC zeta。然而，这种信号通路在β细胞中的作用仍处于早期阶段。PKC ？在体外和体内葡萄糖介导的β细胞增殖和功能中起关键作用？我们的初步结果表明葡萄糖确实需要PKC ？增加小鼠和人β细胞体外增殖。此外，PKC ？β细胞导致小鼠和人β细胞增殖和体外小鼠胰岛胰岛素分泌增加。在体内也会发生吗？在目前的建议中，使用一种新的四天葡萄糖输注模型和表达显性阴性或构成活性PKC ？在β细胞中，我们将充分描述PKC ？基础和葡萄糖介导的β细胞生长和功能及其在胰岛移植中的治疗潜力。为了发展这个项目，我们将实现以下具体目标：1。如何界定委员会的角色？葡萄糖介导的β细胞体内增殖。2. 评估PKC组成激活的效果？体外和体内β细胞的增殖、功能和存活。3. 评价PKC组构激活的疗效？在SCID小鼠胰岛移植的边缘质量模型中改善小鼠和人的胰岛移植结果。我们的初步结果表明PKC的核心和关键作用？细胞生长和功能中的信号传导。因此，建议的研究将为PKC的影响提供宝贵的信息。β细胞增殖、功能、存活与胰岛移植。如果翻译成人类，PKC的组成激活？可能是扩大糖尿病患者β细胞质量和功能的一种有吸引力的治疗策略。公共卫生相关性：我们已经表明，生长因子和营养物质如葡萄糖可激活β细胞中的非典型PKC zeta（?）。激活PKC ？结果增加了小鼠，最重要的是，人体外β细胞增殖。目前建议的研究将解释：(i) PKC的影响？体内的β细胞；（ii）私钥合约的运作机制？对细胞的影响；(3)其在胰岛移植中的治疗潜力。建议的研究将提供宝贵的资料，以了解PKC的影响？β细胞增殖、功能、存活与胰岛移植。如果翻译成人类，PKC的激活？可能是扩大糖尿病患者β细胞质量和功能的一种有吸引力的治疗策略。

DESCRIPTION (provided by applicant): Diabetes results from a deficiency of functional beta cells. Studies aimed at analyzing how key growth factors/hormones and intracellular signaling molecules can increase beta cell proliferation, prevent beta cell loss and enhance insulin release are essential for future therapeutic approaches for diabetes. In this proposal, we focus on one of the important downstream targets of phosphatidylinositol 3'-kinase, the atypical protein kinase C (PKC) signaling pathway. Activation of this pathway enhances proliferation, function and survival in numerous cell types. Importantly, in the beta cell, we have shown that growth factors and nutrients such as glucose activate the atypical isoform PKC zeta (?). However, the role of this signaling pathway in the beta cell is still in its early infancy. Is PKC ? crucial in glucose-mediated beta cell proliferation and function in vitro and in vivo? Our preliminary results indicate that glucose indeed requires PKC ? to increase mouse and human beta cell proliferation in vitro. Furthermore, constitutive activation of PKC ? in beta cells results in increased mouse and human beta cell proliferation and insulin secretion in vitro in mouse islets. Does it occur in vivo as well? In the current proposal, using a novel four-day glucose infusion model and transgenic mice expressing dominant-negative or constitutively active PKC ? isoforms in the beta cell, we will fully characterize the role of PKC ? on basal and glucose-mediated beta cell growth and function and its therapeutic potential in an islet transplant setting. To develop this project, we will implement the following Specific Aims: 1. To define the role of PKC ? in glucose-mediated beta cell proliferation in vivo. 2. To assess the effect of constitutive activation of PKC ? in beta cell proliferation, function and survival in vitro and in vivo. 3. To evaluate the efficacy of constitutive activation of PKC ? in improving mouse and human islet transplant outcomes in a marginal mass model of islet transplantation in SCID mice. Our preliminary results demonstrate a central and critical role for PKC ? signaling in beta cell growth and function. Thus, the proposed studies will provide invaluable information on the impact of PKC ? on beta cell proliferation, function, survival and islet transplantation. If translated into humans, constitutive activation of PKC ? may be an attractive therapeutic strategy for expanding beta cell mass and function in patients with diabetes. PUBLIC HEALTH RELEVANCE: We have shown that growth factors and nutrients such as glucose activate atypical PKC zeta (?) in beta cells. Activation of PKC ? results in increased mouse and, most importantly, human beta cell proliferation in vitro. Studies in the current proposal will decipher: (i) the effects of PKC ? in the beta cell in vivo; (ii) the mechanisms underlying PKC ? effects in the beta cell; and, (iii) its therapeutic potential in an islet transplant setting. The proposed studies will provide invaluable information on the impact of PKC ? on beta cell proliferation, function, survival and islet transplantation. If translated into humans, activation of PKC ? may be an attractive therapeutic strategy for expanding beta cell mass and function in patients with diabetes.