Nutrient regulation of stem cell mediated intestinal renewal in Drosophila

干细胞介导的果蝇肠道更新的营养调节

• 批准号: 8215874
• 负责人: Lucy Erin O'brien
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215874
• 关键词: Adult; Age; Animal Model; Area; Brain; Cell Count; Cell Death; Cellular biology; Cessation of life; Diet; Disease; Distant; Drosophila genus; Endocrine; Enterocytes; Epithelial; Equilibrium; Fasting; Genes; Genetic; Genetic Screening; Goals; Health; Homeostasis; Homologous Gene; Injury; Insulin; Insulin Antagonists; Intestines; Intravenous Feeding; Light; Mammals; Mediating; Mentorship; Midgut; Molecular Biology; Multipotent Stem Cells; Nutrient; Organ Size; Organism; Pathway interactions; Physiology; Process; Processed Genes; Regulation; Research; Research Project Grants; Research Training; Role; Signal Transduction; Stem cells; Structure; System; Testing; Tissues; Variant; Work; absorption; deprivation; feeding; flexibility; fly; insight; interest; neuropeptide Y; novel; response; self-renewal; stem cell biology; stem cell division; tool

DESCRIPTION (provided by applicant): Tissue self renewal is essential to the viability of the adult organism. In the intestine, the renewal process has built-in flexibility to adapt to external influences by altering the proliferation/death equilibrium. However, the signals that trigger adaptation and the mechanisms that re-equilibrate homeostatic balance are virtually unexplored. With the recent discovery that multipotent stem cells renew the intestinal lining in the adult Drosophila midgut, the powerful advantages of the Drosophila system-superior genetic tools, sophisticated cellular analysis, and high experimental tractability-can be applied to the outstanding problem of how tissue homeostasis is dynamically regulated. The ultimate goals of this research are to understand how death and proliferation are coordinated within tissues to achieve homeostasis and to uncover the mechanisms that enable homeostatic flexibility. This proposal focuses on nutrient-driven mucosal remodeling, a paradigm of intestinal adaptation. Combined genetic and cellular approaches will be used to examine the hypothesis that distinct systemic and local mechanisms regulate nutrient-driven adaptation. Aim 1 will characterize how nutrients alter the spatial and temporal profile of the proliferaton [sic]/death balance in intestinal homeostasis. Aim 2 will investigate the role of systemic, nutrient-sensitive endocrine signals, particularly insulin and a Drosophila neuropeptide Y homolog, in homeostatic remodeling. Aim 3 will investigate the role of local cellular interactions by determining how enterocytes act through tissue structure to control the proliferation of nearby stem cells, culminating in a genetic screen to identify novel genes, both nutrient-sensitive and -insensitive, that promote short-range homeostatic control. The results from these studies will shed new light on the pathways that underlie intestinal adaptation. Under the mentorship of Dr. David Bilder and co-mentorship of Dr. John Forte, both leaders in the irrespective fields, the candidate will gain expertise in newer areas of GI physiology, stem cell biology, and genetic screening while pursuing her long-standing interest in epithelial tissue dynamics. This research and training plan will faciliate [sic] the candidate's progression to autonomy by helping her establish an independent and complementary research project within the UC Berkeley Department of Molecular and Cell Biology. PUBLIC HEALTH RELEVANCE: The ability of the intestine to renew itself can be overwhelmed by injury and disease, leading to impaired nutrient absorption and long-term intravenous feeding. To develop better therapies, we need to know more about the basic genes and processes that control intestinal renewal. Studying intestinal renewal in fruit flies, a simple animal model, will generate new leads that can be explored further in mammals.

描述（由申请人提供）： 组织自我更新对于成人生物的生存能力至关重要。在肠道中，更新过程具有内置的灵活性，可以通过改变增殖/死亡平衡来适应外部影响。但是，几乎没有探索触发适应性的信号和重新平衡稳态平衡的机制。随着最近的发现，多能干细胞更新成年果蝇中心的肠壁，果蝇系统 - 遗传学工具的强大优势，精致的细胞分析和高实验性的可触觉 - can被应用于组织稳态如何动态调节的杰出问题。这项研究的最终目标是了解如何在组织中协调死亡和增殖以实现体内稳态并揭示能够稳态灵活性的机制。该提案着重于营养驱动的粘膜重塑，这是肠道适应的范式。结合遗传和细胞方法将用于检验以下假设：独特的全身和局部机制调节营养驱动的适应性。 AIM 1将表征养分如何改变肠内稳态中增殖[SIC]/死亡平衡的空间和时间谱。 AIM 2将研究系统性，营养敏感的内分泌信号，尤其是胰岛素和果蝇神经肽y同源物在稳态重塑中的作用。 AIM 3将通过确定肠细胞如何通过组织结构起作用以控制附近干细胞的增殖，从而在遗传筛选中识别新颖的基因，从而促进短距离稳态控制。这些研究的结果将为肠道适应的途径提供新的启示。在戴维·比尔德（David Bilder）博士和约翰·福尔特（John Forte）博士的指导下，无论领域如何，候选人都将在GI生理学，干细胞生物学和遗传筛查的新领域获得专业知识，同时追求她对上皮组织动力学的长期兴趣。这项研究和培训计划将通过帮助她在分子和细胞生物学分子和细胞生物学系内建立独立和互补的研究项目来促进候选人的自治发展。 公共卫生相关性：肠子本身更新本身的能力可能会因损伤和疾病而淹没，从而导致营养吸收和长期静脉注射喂养受损。为了开发更好的疗法，我们需要更多地了解控制肠道更新的基本基因和过程。研究果蝇中的肠道更新是一种简单的动物模型，将产生新的潜在客户，可以在哺乳动物中进一步探索。