Pancreatic Islet Growth Factors: Transgenic and Viral Modeling

胰岛生长因子：转基因和病毒模型

• 批准号: 8636445
• 负责人: ANDREW F. STEWART
• 金额: $ 36.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-11-19 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636445
• 关键词: Address; Automobile Driving; Award; Beta Cell; Biology; CDKN1C gene; CDKN2A gene; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell physiology; Cyclin A; Data; Development; Diabetes Mellitus; Epidemic; Faculty; Family suidae; Functional disorder; Genetic Transcription; Glucose; Goals; Grant; Growth Factor; Hepatocyte Growth Factor; Human; Immune; Islets of Langerhans; Knock-out; Lead; Light; Menin; Methods; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Nutrient; Pathway interactions; Physiology; Placental Lactogen; Postdoctoral Fellow; Progress Reports; Proteins; Proteome; Rattus; Refractory; Repression; Research Personnel; Rodent; Rodent Control; Role; Signal Pathway; Signal Transduction; Source; Structure of beta Cell of islet; System; Therapeutic; Transgenic Organisms; United States National Institutes of Health; Viral; base; beta cell replacement; blood glucose regulation; c-Myc Staining Method; cyclin-dependent kinase inhibitor 1B; diabetic; human embryonic stem cell; induced pluripotent stem cell; insight; insulinoma; interest; islet; mouse model; nonhuman primate; overexpression; p107 protein; parathyroid hormone-related protein; prevent; response; small molecule; treatment strategy; type I and type II diabetes

DESCRIPTION (provided by applicant): This is an A-1 revision of a competing continuation application for DK55023 which has been active for the past 10 years, and which has served as the basis for the PI's exploration of growth factor, signaling and cell cycle control in the pancreatic beta cell. It is now clear that both Type 1 as well as Type 2 diabetes result in part or entirely from beta cell deficiency and/or dysfunction, and that beta cell replacement can reverse diabetes in humans. The two major hurdles to beta cell replacement and regeneration are now an incomplete ability to prevent auto- and allo-immune attack, and a grossly inadequate supply of human beta cells. This renewal application addresses the second hurdle. While it is now abundantly clear that it is possible to activate rodent beta cell replication, human beta cells remain refractory to replication induced by growth factors, nutrients, and signaling pathway activation. Our group has characterized the murine and human beta cell cycle control machinery and has developed cell-cycle based approaches to driving robust human beta cell replication. In this application, we describe studies focused on three interesting and surprising cell cycle regulators that have emerged from prior versions of this grant: p57, cMyc and p107. Most investigators would not intuitively have selected these three as likely candidates for normal cell cycle control and human beta cell expansion. We believe that the data presented herein move them from among the least interesting to among the most interesting and potentially important candidates for regulating beta cell proliferation in rodents and humans. Thus, the Specific Aims of this proposal are: Specific Aim 1. To Define the Importance of p57 in Restraining Rodent and Human Beta Cell Replication. Specific Aim 2. To Define the Pathophysiology and Therapeutic Potential of Mild, Graded and Transient cMyc Overexpression in Rat and Human Beta Cells. Specific Aim 3. To Define the Relevance of the Pocket Protein, p107, in Mouse and Human Beta Cell Cycle Repression. These studies should provide important insight into how beta cell replication is controlled and lead to insight into how one might develop methods to activate these key molecules in the human beta cell, and permit inducible, regulated human beta cell replication.

描述（由申请人提供）：这是 DK55023 竞争性延续申请的 A-1 修订版，该申请在过去 10 年中一直处于活跃状态，并且已成为 PI 对胰腺 β 细胞中生长因子、信号传导和细胞周期控制的探索的基础。现在已经清楚，1 型和 2 型糖尿病都部分或完全由 β 细胞缺陷和/或功能障碍引起，并且 β 细胞替代可以逆转人类糖尿病。目前，β细胞替代和再生的两个主要障碍是预防自身和同种免疫攻击的能力不完全，以及人类β细胞的供应严重不足。该续订申请解决了第二个障碍。虽然现在非常清楚，激活啮齿动物 β 细胞复制是可能的，但人类 β 细胞仍然难以抵抗生长因子、营养物质和信号通路激活诱导的复制。我们的团队已经表征了小鼠和人类 β 细胞周期控制机制，并开发了基于细胞周期的方法来驱动强大的人类 β 细胞复制。在此申请中，我们描述了针对三种有趣且令人惊讶的细胞周期调节因子的研究，这些调节因子是从本次资助的先前版本中出现的：p57、cMyc 和 p107。大多数研究人员不会凭直觉选择这三种作为正常细胞周期控制和人类β细胞扩增的可能候选者。我们相信，本文提供的数据将它们从最不感兴趣的候选者转变为最有趣且可能最重要的调节啮齿动物和人类β细胞增殖的候选者之一。因此，该提案的具体目标是： 具体目标 1. 明确 p57 在抑制啮齿动物和人类 Beta 细胞复制中的重要性。具体目标 2. 明确大鼠和人类 Beta 细胞中轻度、分级和短暂的 cMyc 过表达的病理生理学和治疗潜力。具体目标 3. 确定口袋蛋白 p107 在小鼠和人类 Beta 细胞周期抑制中的相关性。这些研究应该为如何控制 β 细胞复制提供重要的见解，并深入了解如何开发方法来激活人类 β 细胞中的这些关键分子，并允许可诱导的、受调节的人类 β 细胞复制。