Uncovering mechanisms controlling germline stem cell competition

揭示控制生殖干细胞竞争的机制

• 批准号: 9454752
• 负责人: Erika A Bach
• 金额: $ 8.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454752
• 关键词: Address; Adhesions; Anatomy; Basal lamina; Behavior; Binding; Biological Process; Cancer Etiology; Cell Therapy; Cells; Clone Cells; Collagen Type IV; Competitive Behavior; Cyst; Data; Deposition; Developed Countries; Developing Countries; Disadvantaged; Disease; Drosophila genus; Dystroglycan; Ensure; Evolution; Extinction (Psychology); Extracellular Matrix; Gametogenesis; Gene Targeting; Generations; Genes; Genetic; Genetic Techniques; Germ Cells; Human; Immune; Integrins; Life; Ligands; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Meiosis; Modeling; Molecular; Muscle; Mutation; Organism; Paternal Age; Play; Probability; Procollagen-Proline Dioxygenase; Proteins; Recruitment Activity; Regenerative Medicine; Reproductive Biology; Resistance; Role; Signal Transduction; Stem cells; Stress; Testing; Testis; Tissues; Transcript; Transcription Repressor/Corepressor; Transcriptional Regulation; Work; age effect; cell behavior; cell type; design; fitness; genetic information; germline stem cells; heparin proteoglycan; in vivo; insight; male; mouse model; mutant; novel; offspring; perlecan; self-renewal; sperm cell; stem cell niche; stem cell population; success; transcriptome sequencing

Project Summary The molecular mechanisms controlling stem cell self-renewal, competition and differentiation hold great potential for advances in treating cancer, and in regenerative medicine and in stem cell-based therapies. Stem cells reside in specialized, quiescent microenvironments called niches that secrete short-range signals promoting the maintenance of resident stem cells. Much is known about what regulates the autonomous behaviors within each stem cell type. However, much less is known about the competitive behaviors of between stem cells. The Drosophila testis is one of the best characterized paradigms for investigating stem cell behavior. In this tissue, a single quiescent niche supports two stem cell populations: germline stem cells (GSCs), which give rise to sperm, and somatic cyst stem cells (CySCs), which produce cyst cells. Prior work has shown that GSCs compete with each other for limited space at the niche, but little is known about molecular mechanisms controlling this cooperativity. This proposal reveals the first mutation that endows a male GSC with the ability to out-compete its wild-type neighbors and colonize the testis stem cell niche. The preliminary data in this application show that a competitive GSC and its descendants in the Drosophila testis disadvantage their wild-type neighbors by altering the niche milieu. Additionally, the competitive GSCs remain immune to these alterations by upregulating adhesion factors. Sophisticated genetic techniques in Drosophila will be used to achieve the aims in this proposal. Aim 1 is focused on the transcriptional regulation of extracellular matrix factors in competitive GSCs. Aim 2 will test the model that competitive GSCs have increased adhesion, thus allowing them to remain in the niche while their wild-type neighbors differentiate. We envision this work will impact human reproductive biology and regenerative medicine.

项目摘要 控制干细胞自我更新，竞争和分化的分子机制很大 治疗癌症，再生医学和干细胞疗法的潜力。干 细胞居住在称为壁ni的专业，静止的微环境中，分泌短距离信号 促进居民干细胞的维护。关于自主权的规范知之甚少 每种干细胞类型中的行为。但是，关于竞争行为的了解少得多 在干细胞之间。果蝇睾丸是研究干细胞的最佳特征范例之一 行为。在该组织中，一个静态的小众球体支持两个干细胞种群：种系干细胞 （GSC），产生精子，以及产生囊肿细胞的体细胞干细胞（CYSC）。先前的工作 已经表明，GSC互相竞争在利基市场上有限的空间，但对 控制这种合作的分子机制。该提议揭示了第一个突变 男性GSC具有超越其野生型邻居并定居睾丸干细胞生态位的能力。这 本应用程序中的初步数据表明，竞争性GSC及其后代在果蝇睾丸中 通过改变利基环境，不利他们的野生型邻居。此外，竞争性GSC仍然 通过上调粘附因子来免疫这些改变。果蝇中精致的遗传技术 将用于实现该提案中的目标。 AIM 1专注于转录调节 竞争性GSC中的细胞外基质因子。 AIM 2将测试竞争性GSC的模型 增加的粘附力，从而使它们能够留在利基市场，而野生型邻居则分化。我们 设想这项工作将影响人类生殖生物学和再生医学。