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

蛋白激酶 C (PKC) Zeta 和胰腺 Beta 细胞

• 批准号: 7674801
• 负责人: Adolfo Garcia-Ocana
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674801
• 关键词: 1-Phosphatidylinositol 3-Kinase; Apoptosis; Beta Cell; Cell Death; Cell Proliferation; Cell physiology; Cells; Data; Diabetes Mellitus; Dominant-Negative Mutation; Event; Future; Glucose; Growth Factor; Hepatocyte Growth Factor; Hormones; Human; Hyperplasia; In Vitro; Infusion procedures; Insulin; Islet Cell; Islets of Langerhans Transplantation; Mediating; Mediator of activation protein; Modeling; Mus; NF-kappa B; Natural Killer Cells; Nutrient; Outcome; Pathway interactions; Patients; Performance; Play; Protein Isoforms; Protein Kinase C; Rodent; Role; SCID Mice; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulation of Cell Proliferation; Structure of beta Cell of islet; Study Section; Therapeutic; Transgenic Mice; Translating; Transplantation; Tumor Necrosis Factor Ligand Superfamily Member 6; atypical protein kinase C; cell growth; cell type; citrate carrier; glucagon-like peptide 1; improved; in vivo; infancy; insulin secretion; islet; novel; overexpression; parathyroid hormone-related protein; prevent; protein kinase C zeta; public health relevance

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.

描述（由申请人提供）：糖尿病是由于功能β细胞的缺乏而引起的。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细胞丢失和增强胰岛素释放对于未来的糖尿病治疗方法至关重要的研究。在此提案中，我们关注磷脂酰肌醇3'-激酶的重要下游靶标之一，即非典型蛋白激酶C（PKC）信号通路。该途径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，我们已经表明，葡萄糖等生长因子和养分激活了非典型的同工型PKC Zeta（？）。但是，该信号通路在β细胞中的作用仍处于起步阶段。是PKC吗？在葡萄糖介导的β细胞增殖中至关重要的体外和体内功能？我们的初步结果表明葡萄糖确实需要PKC吗？在体外增加小鼠和人β细胞的增殖。此外，PKC的构成激活？在β细胞中，小鼠胰岛中的小鼠和人β细胞增殖和胰岛素分泌增加。它也发生在体内吗？在当前的建议中，使用一种新型的四天葡萄糖输注模型和表达显性阴性或组成型活性PKC的转基因小鼠？ β细胞中的同工型，我们将充分表征PKC的作用？在基底和葡萄糖介导的β细胞生长和功能以及其在胰岛移植设置中的治疗潜力。为了开发该项目，我们将实施以下特定目标：1。定义PKC的作用？在葡萄糖介导的体内β细胞增殖中。 2。评估PKC构成激活的影响？在β细胞增殖中，体外和体内的功能和存活。 3。评估PKC构型激活的功效？在改善小鼠胰岛移植的边际质量模型中，在改善小鼠和人类胰岛移植结果中。我们的初步结果表明了PKC的核心和关键作用？ β细胞生长和功能中的信号传导。因此，拟议的研究将提供有关PKC影响的宝贵信息？在β细胞增殖，功能，生存和胰岛移植上。如果被翻译成人类，PKC的构成激活？可能是糖尿病患者扩大β细胞量和功能的有吸引力的治疗策略。公共卫生相关性：我们已经表明，β细胞中的生长因子和营养素（例如葡萄糖）激活了非典型PKC Zeta（？）。 PKC的激活？导致小鼠增加，最重要的是在体外人类β细胞增殖。当前建议中的研究将解密：（i）PKC的影响？在体内的β细胞中； （ii）PKC的基础机制？ β细胞的影响； （iii）在胰岛移植设置中其治疗潜力。拟议的研究将提供有关PKC影响的宝贵信息？在β细胞增殖，功能，生存和胰岛移植上。如果被翻译成人类，请激活PKC？可能是糖尿病患者扩大β细胞量和功能的有吸引力的治疗策略。