Mechanisms Controlling Epithelial Homeostasis

控制上皮稳态的机制

基本信息

批准号：
9240655
负责人：
Alana M O'Reilly
金额：
$ 37.5万
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/9240655
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 Defect Degenerative Disorder Development Diabetes Mellitus Diet Dietary Cholesterol Dimerization Disease Distant Drosophila genus Epithelial Erinaceidae Event Food Genes Genetic Genetic Screening Genetic Transcription Germ Cells Global Change Goals Homeostasis Ingestion Integrins Lead Length Ligands Maintenance Malignant Neoplasms Mediating Modeling Molecular 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（由适用提供）：干细胞的长期维护和功能取决于局部干细胞微环境或利基市场产生的信号。尽管在确定干细胞调节所需的利基生成因素方面取得了重大进展，但对控制干细胞对全身变化（例如营养状况）的反应的机制知之甚少。在卵巢中，种系干细胞（GSC）和卵泡干细胞（FSC）在存在丰富的食物的情况下会积极地增殖，但是当营养受到限制时，会迅速到达增殖。最近，我们分子定义了将养分状态变化转化为FSC增殖控制的机制。具体而言，我们发现饮食中胆固醇触发刺猬（HH）分子的释放，该分子被HH结合蛋白BOI隔离在卵巢中HH产生细胞表面上。 HH配体在FSC小众中的积累驱动FSC增殖。该机制使对养分可用性的全球变化产生了快速，特定于组织的反应，从而将卵巢干细胞分裂和卵的产生定制到足以使后代生存的环境条件下。此外，我们的初步工作发现了FSC扩展的小说，类似轴突的细胞投影，这些投影以整合素的方式起作用，以实现FSC分裂，并建立将FSC女儿定位在利基市场中的投影的轨道。 FSC项目与子细胞和种系囊肿联系，这表明FSC项目在介导FSC小众内细胞类型之间的通信中的作用。像整联蛋白突变一样，FSC利基市场内HH信号水平的变化会导致FSC项目的方向性，数量和长度缺陷，这表明HH信号在调节投影形态和维持中的关键作用。基于这些结果，我们建议HH在两步过程中定制FSC划分和卵的产生，以使养分可用性的全身变化，包括1）BOI介导的HH隔离/释放/释放和2）随后通过调节FSC投射动力学调节FSC ni基之间的细胞之间的通信。