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

果蝇损伤诱导的肠道干细胞分裂的遗传分析

• 批准号: 8071233
• 负责人: Y. Tony Ip
• 金额: $ 30.41万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-17 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071233
• 关键词: Adult; Biological Models; Cell Maintenance; Cell Size; Cell division; Cells; Complex; Disease; Drosophila genus; Endocrine; Epithelial Cells; Equilibrium; Essential Genes; GTPase-Activating Proteins; Gastrointestinal tract structure; Genes; Genetic; Genetic Models; Genetic Screening; Genome; Goals; Health; Homologous Gene; Hormones; Human; Immune; Immunologic Surveillance; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Insulin; Insulin Receptor; Intestinal Diseases; Intestines; Intrinsic factor; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Microarray Analysis; Microbe; Midgut; Modeling; Molecular; Molecular Genetics; Mutate; Nutrient; Organ; PTEN gene; Pathway interactions; Peptides; Phenotype; Population; Process; RNA Interference; Receptor Signaling; Regulation; Relative (related person); Reporting; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cells; Stimulus; System; Testing; Therapeutic; Tissues; Transgenic Organisms; Tuberous sclerosis protein complex; Wound Healing; absorption; base; cell growth; cell type; commensal microbes; experience; feeding; fly; genetic analysis; human FRAP1 protein; human disease; human stem cells; insight; insulin signaling; mutant; novel; novel strategies; overexpression; precursor cell; public health relevance; repaired; response; stem cell biology; stem cell division; tissue regeneration; tool; tumor progression

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. PUBLIC HEALTH RELEVANCE: We plan to establish Drosophila intestinal stem cell as a novel genetic model system to study gastrointestinal tract interaction with pathogenic stimuli and tissue regeneration. The human gastrointestinal tract is the major nutrient absorption organ that also has immune and endocrine function. It is also a major site for interaction with commensal bacteria and pathogenic substances. The human gastrointestinal tract is a relatively under-explored organ due to the complexity of the organ and the difficulty in experimental manipulation. Drosophila, the common fruit fly, has emerged as a powerful tool for analyzing the function of human disease genes, either as fly homologues or by expressing in transgenic flies the mutated forms of human genes. To study how intestinal stem cells in Drosophila respond to tissue damage and initiate repair will provide important insights into similar processes in humans. The information obtained may yield novel strategies for treatment of inflammatory diseases and cancer.

描述(申请人提供)：大约1%的美国人患有炎症性肠病。长期的炎症和组织损伤也被认为是胃肠道(GI)癌的致癌因素。了解胃肠道细胞如何与多种微生物和致病物质相互作用，对于制定减轻肠道疾病的治疗策略非常重要。这项建议侧重于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结构，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可以提高它们的分裂率，以响应组织损伤。使用这一新建立的系统，胰岛素受体的遗传需求清楚地表明对ISC的分裂是必不可少的。通过试点基因筛查，还发现了一些可以调控ISC生长和分裂的新基因。由于这个果蝇ISC系统是一个相对较新的系统，目前已知涉及的基因很少，因此首先用遗传学的方法识别更多的必需基因，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响应环境挑战和调节组织修复的分子机制。这一建议包括三个具体目标：1.测试胰岛素信号在ISC分裂中的指导性或允许性；2.研究结节性硬化症复合体与胰岛素途径在ISC生长中的相互作用；3.识别和分析损伤诱导的ISC分裂中的新成分。研究遗传适应性果蝇ISCs的结果将为人类干细胞介导的组织修复、肠道炎症性疾病和癌症进展提供重要的见解。 公共卫生相关性：我们计划建立果蝇肠道干细胞作为一种新的遗传模型系统，以研究胃肠道与致病刺激的相互作用和组织再生。人体胃肠道是人体主要的营养吸收器官，具有免疫和内分泌功能。它也是与共生细菌和致病物质相互作用的主要场所。由于人体胃肠道器官的复杂性和实验操作的难度，它是一个相对较少被研究的器官。果蝇是一种常见的果蝇，它已经成为分析人类疾病基因功能的有力工具，无论是作为果蝇的同源物，还是通过在转基因果蝇中表达人类基因的突变形式。研究果蝇的肠道干细胞如何对组织损伤做出反应并启动修复，将为人类类似的过程提供重要的见解。所获得的信息可能会产生治疗炎症性疾病和癌症的新策略。