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: 8470622
• 负责人: ANDREW F. STEWART
• 金额: $ 33.62万
• 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/8470622
• 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DK 55023的竞争性延续申请的A-1修订版，DK 55023在过去10年中一直处于活跃状态，并作为PI探索胰腺β细胞中生长因子、信号传导和细胞周期控制的基础。现在很清楚，1型和2型糖尿病都部分或完全由β细胞缺乏和/或功能障碍引起，β细胞替代可以逆转人类糖尿病。β细胞替代和再生的两个主要障碍是防止自身和同种免疫攻击的能力不完全，以及人类β细胞供应严重不足。这一更新申请解决了第二个障碍。虽然现在非常清楚的是，有可能激活啮齿动物β细胞复制，但人类β细胞对由生长因子、营养素和信号传导途径激活诱导的复制仍然是难治的。我们的小组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。在本申请中，我们描述了专注于三个有趣和令人惊讶的细胞周期调节因子的研究，这些调节因子是从该资助的先前版本中出现的：p57，cMyc和p107。大多数研究人员不会直观地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有趣的调节啮齿动物和人类β细胞增殖的候选者之一转变为最有趣且潜在重要的候选者之一。因此，本提案的具体目标是：具体目标1。p57在抑制啮齿动物和人类β细胞复制中的重要性具体目标2。确定大鼠和人β细胞中轻度、分级和短暂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β细胞周期抑制中的相关性。这些研究应该提供重要的洞察力β细胞复制是如何控制的，并导致洞察如何开发方法来激活人类β细胞中的这些关键分子，并允许诱导，调节人类β细胞复制。