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: 8583716
• 负责人: ANDREW F. STEWART
• 金额: $ 23.23万
• 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/8583716
• 关键词: Pancreatic; Islet; Growth; Factors; Transgenic

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）：这是对DK55023的竞争连续申请的A-1修订，该应用在过去10年中一直活跃，并且一直是PI探索胰腺β细胞中PI探索生长因子，信号传导和细胞周期控制的基础。现在很明显，型1和2型糖尿病都因β细胞缺乏症和/或功能障碍而部分或全部导致，并且β细胞替代可以逆转人类中的糖尿病。现在，beta细胞更换和再生的两个主要障碍是防止自动和异常免疫攻击以及人类β细胞供应严重不足的不完整能力。此续签应用程序解决了第二个障碍。尽管现在很清楚地表明可以激活啮齿动物β细胞的复制，但人β细胞仍然难治性地对生长因子，养分和信号传导途径激活引起的复制。我们的小组表征了鼠和人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β细胞复制。在此应用程序中，我们描述了研究的研究，这些研究集中在三个有趣且令人惊讶的细胞周期调节器上，这些调节剂已从该赠款的先前版本中出现：P57，CMYC和P107。大多数研究者不会直观地选择这三个可能的候选者来进行正常的细胞周期控制和人类β细胞扩张。我们认为，此处介绍的数据将它们从最不有趣的候选者中移至最不有趣，最重要的候选者中，以调节啮齿动物和人类中的β细胞扩散。因此，该提案的具体目的是：特定目的1。定义p57在限制啮齿动物和人类β细胞复制中的重要性。具体目的2。定义大鼠和人β细胞中轻度，分级和瞬时CMYC过表达的病理生理学和治疗潜力。特定目的3。定义小鼠和人β细胞周期抑制中袋蛋白P107的相关性。这些研究应提供有关如何控制β细胞复制的重要洞察力，并使您可以深入了解人们如何开发在人β细胞中激活这些关键分子的方法，并允许可诱导的，受调节的人类β细胞复制。