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性疾病。长期的炎症和组织损伤也被认为是增强胃肠道（GI）癌症的原因。了解胃肠道细胞如何与各种微生物和致病物质相互作用，对于开发缓解肠道疾病的治疗策略非常重要。这项提案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，并且中肠ISCs最近被鉴定出具有补充不同细胞类型的功能。我们的初步研究结果表明，果蝇ISCs可以增加其分裂率，以应对组织损伤。使用这个新建立的系统，胰岛素受体的遗传需求清楚地表明是必要的ISC分裂。一些新的基因，可以调节ISC的生长和分裂也已确定通过试点遗传筛选。由于果蝇ISC系统是一个相对较新的系统，而且目前已知的基因很少，因此首先通过遗传学方法鉴定更多的必需基因并建立调控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应对环境挑战和介导组织修复的分子机制。该提案包括三个具体目标：1.检验胰岛素信号在ISC区是指导性的还是许可性的; 2.探讨在ISC生长过程中，血管硬化症复合体与胰岛素通路的相互作用;识别和分析损伤引起的ISC分裂中的新成分。从研究遗传上顺从的果蝇ISCs获得的结果应该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.