Mechanisms Controlling Epithelial Homeostasis

控制上皮稳态的机制

基本信息

批准号：
9105077
负责人：
Alana M O'Reilly
金额：
$ 36.61万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-14 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105077
关键词：
Affect Apical Axon BCAR1 gene Binding Binding Proteins Cell Cycle Cell Differentiation process Cell Proliferation Cell physiology Cells Cholesterol Communication Cues Cyst Cytoplasmic Tail Daughter Defect Degenerative Disorder Development Diabetes Mellitus Diet Dietary Cholesterol Disease Distant Drosophila genus Epithelial Erinaceidae Event Food Genes Genetic Genetic Screening Germ Cells Global Change Goals Homeostasis Ingestion Integrins Lead Length Ligands Maintenance Malignant Neoplasms Mediating Modeling Morphology Mutation Normal tissue morphology Nutrient Nutritional Nutritional status Organism Ovarian Ovarian Follicle Ovary Phosphorylation Positioning Attribute Premature aging syndrome Process Production Proliferating Proteins Regulation Repression Ribosomal Protein S6 Kinase Role Signal Transduction Somatic Cell Stem cells Surface Testing Tissues Transcriptional Activation Translating Traumatic injury Wing Work adult stem cell base cdc Genes cell behavior cell type daughter cell dimer egg feeding fly germline stem cells novel patched protein prevent public health relevance receptor response smoothened signaling pathway src-Family Kinases stem cell division stem cell niche stem cell therapy

项目摘要

DESCRIPTION (provided by applicant): The long term maintenance and function of stem cells depend on signals generated by the local stem cell microenvironment, or niche. While significant progress has been made in identifying the niche-generated factors necessary for stem cell regulation, little is known about the mechanisms that control stem cell responses to systemic changes such as nutritional status. In the fly ovary, germline stem cells (GSCs) and follicle stem cells (FSCs) proliferate actively in the presence of abundant food, but rapidly arres proliferation when nutrients are limited. Recently, we molecularly defined the mechanism that translates changes in nutrient status to FSC proliferation control. Specifically, we found that dietary cholesterol triggers release of Hedgehog (Hh) molecules sequestered by the Hh binding protein Boi on the surface of Hh-producing cells within the ovary. The resulting accumulation of Hh ligand in the FSC niche drives FSC proliferation. This mechanism enables a rapid, tissue-specific response to global changes in nutrient availability, thus tailoring ovarian stem cell divisions and egg production to environmental conditions that are sufficient for progeny survival. In addition, our preliminary work uncovers novel, axon-like cellular projections extended by FSCs that act in an integrin-dependent manner to orient FSC division and establish tracks of projections that position FSC daughters within the niche. FSC projections contact daughter cells and germline cysts, suggesting a role for FSC projections in mediating communication between cell types within the FSC niche. Like integrin mutation, changes in Hh signaling levels within the FSC niche lead to defects in the directionality, number, and length of FSC projections, suggesting a critical role for Hh signaling in regulation of projection morphology and maintenance. Based on these results, we propose that Hh tailors FSC divisions and egg production to systemic changes in nutrient availability in a two-step process that includes 1) Boi-mediated Hh sequestration/release and 2) subsequent regulation of communication between cells within the FSC niche via regulation of FSC projection dynamics.

描述（由申请人提供）：干细胞的长期维持和功能取决于局部干细胞微环境或生态位产生的信号，尽管在识别干细胞调节所需的生态位生成因子方面取得了重大进展，但进展甚微。众所周知，控制干细胞对系统变化（例如营养状况）做出反应的机制在果蝇卵巢中，生殖干细胞（GSC）和卵泡干细胞（FSC）在食物丰富的情况下会活跃地增殖，但增殖速度很快。最近，我们从分子角度定义了将营养状态的变化转化为 FSC 增殖控制的机制，具体来说，我们发现膳食胆固醇会触发 Hh 结合蛋白 Boi 释放在表面。由此产生的 Hh 配体在 FSC 生态位中的积累驱动 FSC 增殖，从而能够对营养可用性的整体变化做出快速、组织特异性的反应，从而调整卵巢。此外，我们的初步工作揭示了 FSC 延伸的新型轴突样细胞投射，这些投射以整合素依赖的方式定向 FSC 分裂并建立投射轨迹。 FSC 子细胞在生态位中的位置与子细胞和种系囊肿相关，这表明 FSC 预测在介导 FSC 生态位内细胞类型之间的通讯方面发挥着作用，就像整合素突变和 Hh 的变化一样。 FSC 生态位内的信号水平导致 FSC 投射的方向性、数量和长度缺陷，表明 Hh 信号在投射形态和维持的调节中发挥关键作用。基于这些结果，我们建议 Hh 定制 FSC 分裂和卵。生产对营养物质可用性的系统性变化有两个步骤，包括 1) Boi 介导的 Hh 封存/释放和 2) 随后通过调节 FSC 投射动力学来调节 FSC 生态位内细胞之间的通讯。