Elucidating function of the novel PINX1-related protein, Chigno, in reproductive stem cells and development

阐明新型 PINX1 相关蛋白 Chigno 在生殖干细胞和发育中的功能

• 批准号: 10730857
• 负责人: MATTHEW J WAWERSIK
• 金额: $ 43.35万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730857
• 关键词: Adult; Apical; Authorship; Basic Science; Behavior; Binding; Binding Proteins; Cell Differentiation process; Cell Maintenance; Cell physiology; Cells; Cessation of life; Chronology; Communication; Contraceptive methods; Cyst; Data; Daughter; Development; Drosophila genus; Drosophila melanogaster; Educational process of instructing; Embryo; Ensure; Environment; Epithelial Cells; Equilibrium; Fertility; Fostering; Future; Gene Expression; Genes; Germ Cells; Germ cell tumor; Goals; Gonadal structure; Grant; Homeostasis; Human; Human Development; Infertility; Link; Maintenance; Malignant Neoplasms; Mammals; Maps; Methodology; Molecular; Morphogenesis; Organ; Organism; Ovary; Pattern; Process; Production; Proteins; Records; Regulation; Repression; Research; Research Personnel; Research Training; Resources; Role; Scholarship; Students; System; Testing; Testis; Tissues; Training; Tumor Suppressor Proteins; Work; career; cell behavior; developmental disease; embryo tissue; experimental study; fly; gene regulatory network; germline stem cells; human disease; in vivo; knock-down; neuronal cell body; novel; prevent; programs; protein function; protein protein interaction; reproductive; senescence; stem cell niche; stem cell self renewal; stem cells; student participation; student training; success; symposium; training opportunity; transcription factor; tumor; undergraduate student

PROJECT SUMMARY: The germline stem cell (GSC) niche functions to ensure continuous gamete production in organisms that reproduce sexually. Dysregulation of stem cells has also been linked to developmental disorders, cancer, infertility, and senescence. In flies and mammals alike, communication between GSCs and the surrounding soma regulates the balance between stem cell maintenance and differentiation. However, new and unexplored mechanisms regulating these processes are still being discovered - necessitating further enquiry. This proposal strives to elucidate the function of a novel PINX1-related protein, CG11180/Childless Gambino (Chigno), in regulating reproductive stem cell behavior and development in the fruit fly, Drosophila melanogaster. Chigno is a novel G-patch domain-containing protein in flies that is related to the mammalian tumor suppressor, PINX1. We previously identified Chigno as a binding partner of Chronologically inappropriate morphogenesis (Chinmo), a key regulator of somatic stem cell behavior in the adult Drosophila testis. Preliminary data collected by undergraduate and master’s student researchers in our lab show that Chigno is expressed in larval and adult testes, as well as Drosophila ovaries and early embryos. In adult testes, Chigno is observed specifically at the testis apex, which houses the germline stem cell (GSC) niche. Here, it is detected both in germ cells as well as somatic cyst stem cells (CySCs) and their progeny which regulate germline behavior. We also find that Chigno knockdown in adult CySCs and early cyst cells results in CySC over-production, formation of germ cell tumors, and an expansion of epithelial cells at the testis apex that may be linked to altered CySC identity. Furthermore, somatic Chigno depletion causes both testis and ovaries to become infertile. Experiments in this proposal are focused on understanding the role of Chigno in regulating testis stem cell self-renewal, differentiation, and cell fate maintenance (Aim 1), understanding Chigno protein function at the molecular level (Aim 2), and assessing whether Chigno functions in tissues other than the testis, including Drosophila ovaries and embryonic tissues (Aim 3). Given Chigno’s impact on fertility and testes stem cell behavior, as well as the diverse functions of G-patch/PINX1-related proteins in a range of cellular processes, the proposed studies into Chigno function hold great promise for elucidating novel mechanisms controlling fertility, stem cell behavior, and development in a range of organisms.

项目摘要： 种系干细胞（GSC）利基的功能，以确保生物中的连续配子产生 性繁殖。干细胞的失调也与发展疾病，癌症， 不育和感应。在苍蝇和哺乳动物中，GSC与周围环境之间的交流 SOMA调节干细胞维持和分化之间的平衡。但是，新的和 仍在发现调查这些过程的意外机制 - 必要的查询。 该建议旨在阐明新型PINX1相关蛋白的功能CG11180/无子女Gambino （Chigno），在控制果蝇中的生殖干细胞行为和发育中 Melanogaster。 Chigno是一种与哺乳动物肿瘤有关的新型G-Patch结构域的蛋白质 抑制器，Pinx1。我们先前将Chigno确定为按时间顺序不合适的结合伙伴 形态发生（Chinmo），成年果蝇睾丸中体细胞行为的关键调节剂。 本科和硕士学生研究人员在我们的实验室中收集的初步数据表明，Chigno是 在幼虫和成人测试以及果蝇卵巢和早期胚胎中表达。在成人测试中，Chigno 在睾丸顶端特别观察到，该顶点容纳种系干细胞（GSC）生态位。这里是 在生殖细胞以及体细胞干细胞（CYSC）及其后代都检测到 种系行为。我们还发现，成年CYSC和早期囊肿细胞中的Chigno敲低导致CYSC 过量产生，生殖细胞肿瘤的形成以及睾丸顶点上上皮细胞的扩展 与改变的CYSC身份有关。此外，体细胞的部署会导致睾丸和卵巢 变得不育。 该提案中的实验重点是了解Chigno在调节睾丸茎中的作用 细胞自我更新，分化和细胞命运维持（AIM 1），了解Chigno蛋白功能 分子水平（AIM 2），并评估Chigno是否在睾丸以外的组织中功能，包括 果蝇卵巢和胚胎组织（AIM 3）。考虑到Chigno对生育能力的影响和测试干细胞 行为以及G-PATCH/PINX1相关蛋白在一系列细胞过程中的潜水功能， 对Chigno功能的拟议研究对阐明控制的新机制有很大的希望 一系列生物中的生育能力，干细胞行为和发育。