Lactogens and Pancreatic Beta Cell Survival

泌乳素和胰腺 β 细胞存活

• 批准号: 7677904
• 负责人: Rupangi C Vasavada
• 金额: $ 23.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677904
• 关键词: Beta Cell; Candidate Disease Gene; Cell Death; Cell Proliferation; Cell Survival; Complementary DNA; Diabetes Mellitus; Functional disorder; Future; Goals; Growth Factor; Hepatocyte Growth Factor; Hormones; Hyperplasia; Hypertrophy; Hypoglycemia; In Vitro; Insulin; Islets of Langerhans Transplantation; Knowledge; Longevity; Mus; Nature; Outcome; Outcome Study; Pancreas; Pathway interactions; Performance; Physiological; Physiology; Placental Lactogen; Play; Pregnancy; Prevention; Prolactin; Prolactin Receptor; Rattus; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Source; Streptozocin; Structure of beta Cell of islet; Therapeutic Studies; Transgenic Mice; Translating; Transplantation; cell type; cytotoxic; diabetic patient; endocrine pancreas development; glucagon-like polypeptides; improved; improved functioning; in vivo; islet; mouse model; placental lactogen I; promoter; protective effect; success

DESCRIPTION (provided by applicant): The lactogenic hormones, prolactin (PRL) and placental lactogen (PL), which signal through the prolactin receptor, are important for islet development, for enhancing beta cell proliferation, and for improving islet function in normal physiology as well as during pregnancy. We have developed a transgenic mouse model in which the rat insulin II promoter (RIP) drives expression of murine placental lactogen I (mPL1) cDNA in beta cells. These mice are hypoglycemic and display islet hyperplasia as a result of increased beta cell proliferation and hypertrophy. Although activation of the prolactin receptor improves survival in a number of different cell types, the effect of lactogens on beta cell survival has just begun to be examined. In this context, we have recently demonstrated that PL expression in the beta cell of RIP-mPL1 mice confers resistance to the diabetogenic and cytotoxic effects of streptozotocin in these mice, implying a protective role of mPL1 in beta cells. However, nothing is known regarding the nature, mechanism, and signaling pathways implicated in the protective effect of lactogens on beta cells. Understanding the regulation of beta cell survival is important both in normal physiology, as well as in the pathophysiology of diabetes and islet transplantation. Therefore, the main goals of the current proposal are to understand how lactogen signaling can enhance beta cell survival, to determine the relevance of this pathway in the survival of beta cells under physiological and pathophysiological conditions, and to examine whether the beneficial effects of these hormones can translate into enhanced performance in islet transplantation. The Specific Aims of this proposal are: 1) To define the mechanisms responsible for lactogen-induced survival of beta cells. 2) To establish the physiological significance of lactogen signaling on beta cell survival. 3) To examine the role of lactogens in islet transplant outcomes. The studies in this proposal will further our understanding of the regulation of beta cell death by lactogens. The ultimate objective is to apply this knowledge to select suitable candidate genes for prolonging islet survival in future therapeutic studies in the context of islet transplantation and in the prevention and cure of diabetes.

描述（由申请人提供）：催乳激素、催乳素（PRL）和胎盘催乳素（PL）通过催乳素受体发出信号，对胰岛发育、增强β细胞增殖以及改善正常生理学和妊娠期间的胰岛功能非常重要。我们已经开发了一种转基因小鼠模型，其中大鼠胰岛素II启动子（RIP）驱动鼠胎盘催乳素I（mPL 1）cDNA在β细胞中的表达。这些小鼠是低血糖的，并且由于增加的β细胞增殖和肥大而显示胰岛增生。虽然催乳素受体的激活提高了许多不同类型细胞的存活率，但催乳素对β细胞存活率的影响才刚刚开始研究。在这种情况下，我们最近已经证明，PL表达在β细胞的RIP-mPL 1小鼠赋予耐糖尿病和细胞毒性作用的链脲佐菌素在这些小鼠中，这意味着保护作用的mPL 1 β细胞。 然而，关于催乳素对β细胞的保护作用所涉及的性质、机制和信号传导途径还一无所知。了解β细胞存活的调节在正常生理学以及糖尿病和胰岛移植的病理生理学中都很重要。因此，目前建议的主要目标是了解催乳素信号如何增强β细胞存活，以确定该途径在生理和病理生理条件下β细胞存活的相关性，并检查这些激素的有益作用是否可以转化为胰岛移植中的增强性能。该提案的具体目标是： 1)确定催乳素诱导β细胞存活的机制。 2)建立催乳素信号传导对β细胞存活的生理意义。 3)研究催乳素在胰岛移植结果中的作用。 这项研究将进一步加深我们对催乳素调节β细胞死亡的理解。最终的目标是应用这些知识来选择合适的候选基因，以延长胰岛存活在未来的治疗研究中的背景下，胰岛移植和糖尿病的预防和治疗。