Amitosis of Polyploid Cells to Functional Intestinal Stem Cells

多倍体细胞有丝分裂形成功能性肠干细胞

• 批准号: 9761532
• 负责人: Benjamin Ohlstein
• 金额: $ 36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761532
• 关键词: Address; Aging; Animals; Area; Biological; Biological Assay; Biological Process; Cell Count; Cell Survival; Cell division; Cell physiology; Cells; Cellular biology; Chemicals; Chromosome Segregation; Cues; Data; Drosophila genus; Ectopic Expression; Enterocytes; Face; Family; Fluorescent in Situ Hybridization; Foundations; Frequencies; Future; Gastrointestinal tract structure; Genetic; Genetic Screening; Genomics; Goals; Growth; Homeostasis; Human; Intestines; Link; Malignant Neoplasms; Mammals; Midgut; Modeling; Molecular; Morphology; Mus; Mutation; Nutritional; Organ; Organism; Outcome; Physiological; Ploidies; Polyploid Cells; Polyploidy; Process; Research; Research Project Grants; Research Project Summaries; Research Proposals; Signal Transduction; Snails; Starvation; Stem cells; Stress; Tetrahymena thermophila; Time; Tissue Expansion; Tissues; Work; base; cancer cell; exhaust; exhaustion; experimental study; feeding; fly; functional loss; intestinal epithelium; novel; open data; rab GTP-Binding Proteins; response; response to injury; self-renewal; stem cell biology; stem cell division; stemness; transcription factor

Project Summary The research project described herein seeks to determine the genetics and cell biological mechanisms that drive depolyploidization of enterocytes to functional intestinal stem cells in the Drosophila intestinal epithelium. New stem cells are commonly thought to arise by symmetric division of existing stem cells. However, Preliminary Data demonstrates that rapid and severe depletion of ISCs during the physiological stress of starvation initiates ploidy reduction (depolyploidization) to replace ISCs upon re-feeding. Our Preliminary Data underline the importance in considering dedifferentiation as a more general mechanism of stem cell replacement in other tissues. Our preliminary data open three compelling questions for future study, which we will endeavor to address with the experiments described in this proposal: What conditional states of the ISC invoke the use of depolyploidization (Specific Aim 1)? What signals initiate fate reversion and depolyploidization (Specific Aim 2)? What cell biology drives depolyploidization and at what frequency is genomic fidelity maintained (Specific Aim 3)? As this is truly an uncharted area of research, we anticipate that the mechanisms delineated in the genetically tractable Drosophila model will provide a foundation for future studies in other tissues and organisms.

项目摘要 本文描述的研究项目旨在确定遗传学和细胞生物学机制， 在果蝇肠上皮中驱动肠细胞去多倍化为功能性肠干细胞。 新的干细胞通常被认为是由现有干细胞的对称分裂产生的。然而，在这方面， 初步数据表明，在生理应激期间， 饥饿引发倍性降低（去多倍化）以在再喂养时替换ISC。我们的初步数据 强调将去分化视为干细胞更普遍的机制的重要性 在其他组织中进行替换。我们的初步数据为未来的研究提出了三个引人注目的问题，我们 我将奋进解决与本提案中描述的实验：什么条件状态的ISC 使用去多倍化（具体目标1）？什么信号启动命运逆转， 去多倍化（具体目标2）？什么样的细胞生物学驱动去多倍化，频率是多少？ 保持基因组保真度（特定目标3）？由于这确实是一个未知的研究领域，我们预计， 在遗传上易于处理的果蝇模型中描述的机制将为未来的研究提供基础。 其他组织和生物体的研究。