Genetic analysis of damage-induced intestinal stem cell division in Drosophila

描述（由申请人提供）：大约1%的美国人口患有肠道炎症性疾病。长期的炎症和组织损伤也被认为是促进胃肠道（GI）癌症的因素。了解胃肠道细胞如何与多种微生物和致病物质相互作用，对于制定缓解肠道疾病的治疗策略非常重要。这一建议的重点是了解果蝇肠道干细胞（ISCs）如何介导组织损伤后的修复。果蝇中肠具有相对简单的细胞组织，最近发现中肠ISCs具有补充不同细胞类型的功能。我们的初步结果表明，果蝇ISCs可以提高其分裂率，以应对组织损伤。利用这个新建立的系统，胰岛素受体的遗传要求被清楚地显示为ISC分裂的必要条件。一些可以调节ISC生长和分裂的新基因也已通过试点基因筛选确定。由于果蝇的ISC系统相对较新，目前已知参与的基因很少，因此首先通过遗传学方法确定更多必需基因并建立调节ISC分裂的框架是很重要的。一个完善的遗传框架将有助于理解ISCs响应环境挑战和介导组织修复的分子机制。这一建议包括三个具体目标：1。检测胰岛素信号在ISC分裂中是指导性的还是许可性的；2. 探讨结节性硬化症复合体与胰岛素通路在ISC生长中的相互作用；3. 识别和分析损坏引起的ISC部门的新部件。通过对果蝇ISCs基因的研究获得的结果将为人类干细胞介导的组织修复、肠道炎症疾病和癌症进展提供重要的见解。

DESCRIPTION (provided by applicant): Around 1% of the US population experience inflammatory diseases of the intestine. Prolonged inflammation and tissue injury has also been proposed to potentiate gastrointestinal (GI) cancer. To understand how cells in the GI tract interact with wide varieties of microbes and pathogenic substances is important for developing therapeutic strategies that alleviate intestinal diseases. This proposal focuses on understanding how Drosophila intestinal stem cells (ISCs) mediate repair after tissue damage. Drosophila midgut has a relatively simple cellular organization, and midgut ISCs have recently been identified that function to replenish the different cell types. Our preliminary results demonstrate that Drosophila ISCs can increase their division rate in response to tissue damage. Using this newly established system, the genetic requirement of insulin receptor is clearly shown to be essential for ISC division. A number of new genes that can regulate ISC growth and division have also been identified via a pilot genetic screen. Because this Drosophila ISC system is relative new and so far very few genes are known to be involved, it is important to first identify more essential genes by genetic approach and establish the framework that regulates ISC division. A well-established genetic framework will help to understand the molecular mechanisms by which ISCs respond to environmental challenges and mediate tissue repair. This proposal includes three specific aims: 1. Test whether insulin signaling is instructive or permissive in ISC division; 2. Investigate how Tuberous Sclerosis Complex interacts with the insulin pathway in ISC growth; 3. Identify and analyze new components in damage-induced ISC division. The results obtained from studying the genetically amenable Drosophila ISCs should provide important insights into human stem cell- mediated tissue repair, intestinal inflammatory diseases and cancer progression.