Pancreatic Islet Growth Factors: Transgenic and Viral Modeling

描述(由申请人提供)：这是DK55023竞争延续申请的A-1修订版，该申请在过去10年中一直活跃，并作为PI探索胰腺β细胞中的生长因子、信号传递和细胞周期控制的基础。现在很清楚，1型和2型糖尿病都是部分或全部由β细胞缺陷和/或功能障碍造成的，并且β细胞替代可以逆转人类的糖尿病。目前，贝塔细胞替代和再生的两大障碍是预防自身和同种免疫攻击的能力不完全，以及人类贝塔细胞供应严重不足。这一续签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的β细胞复制，但人类的β细胞仍然对由生长因子、营养物质和信号通路激活所诱导的复制无效。我们的团队已经确定了小鼠和人类β细胞周期控制机制的特征，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。在这项申请中，我们描述了三个有趣和令人惊讶的细胞周期调节因子的研究，它们来自以前的拨款版本：p57，cMyc和p107。大多数研究人员不会直观地选择这三个人作为正常细胞周期控制和人类β细胞扩增的可能候选者。我们认为，本文提供的数据将它们从最不感兴趣的候选对象之一转移到了最感兴趣的和潜在的重要候选对象中，以调控啮齿动物和人类的β细胞增殖。因此，这项建议的具体目标是：具体目标1。明确p57在抑制啮齿动物和人类β细胞复制中的重要性。明确轻度、分级和暂时性cMyc在大鼠和人Beta细胞中过表达的病理生理学和治疗潜力。具体目的3.确定Pocket蛋白p107在小鼠和人β细胞周期抑制中的相关性。这些研究应该为如何控制β细胞复制提供重要的见解，并使人们能够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、受调控的人类β细胞复制。

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.