Post-translational regulation of sperm development and function in C. elegans

秀丽隐杆线虫精子发育和功能的翻译后调控

• 批准号: 10653491
• 负责人: DIANE CAROL SHAKES
• 金额: $ 41.22万
• 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: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653491
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Biochemical; Biological Models; Biology; Bypass; CRISPR/Cas technology; CSNK1A1 gene; Caenorhabditis elegans; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Chromosomes; Collaborations; Complement; Cytoskeletal Proteins; Defect; Development; Developmental Biology; Drug Targeting; Environment; Enzymes; Escherichia coli; Female; Fertility; Fertilization; Gene Duplication; Gene Family; Gene Fusion; Genes; Genetic; Genetic Screening; Genetic Transcription; Giant Cells; Goals; Homologous Gene; Human; Immunofluorescence Immunologic; Impairment; In Vitro; Individual; Infertility; Knock-out; Malignant Neoplasms; Meiosis; Mentors; Metaphase; Microscope; Molecular; Monitor; Morphology; Mutation; Nematoda; Oogenesis; Outcome; Parasites; Pathogenicity; Pathologic; Pathway interactions; Pattern; Persons; Pharmacologic Substance; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Post-Translational Regulation; Process; Proteins; Publishing; Regulation; Research; Residual state; Role; Science; Site; Sperm Motility; Spermatocytes; Spermatogenesis; Students; System; Testing; Training; Transgenic Organisms; Uterus; Work; casein kinase I; cell type; experimental study; fundamental research; gene conservation; human disease; imaging system; in vivo; insight; knock-down; knockout gene; male; member; migration; mutant; novel; programs; protein function; reproductive tract; segregation; sperm cell; sperm function; sperm protein; tau-tubulin kinase; tool; training opportunity; undergraduate research experience; undergraduate student; ward

RELEVANCE: Under both normal and pathological conditions, kinases and phosphatases are key post-translational regulators of cellular and developmental pathways. Mis-regulation of these enzymes is associate with diverse pathologies from Alzheimer's and cancer to infertility. Our studies will investigate a kinase SPE-6 that is related to the Alzheimer's relevant kinase (tau tubulin kinase and a pseudophosphatase SPE-54, a class of enzymes whose critical roles are only recently being recognized. RATIONALE: Our studies will investigate the function of these proteins in the unique context of C. elegans sperm development and sperm function. Because humans and C. elegans share many of the same genes, discoveries made in C. elegans can be directly relevant to humans. Conversely, nematode-specific proteins required for fertility are promising drug targets for sterilizing nematode parasites that infect over a billion people. As an experimental system, the molecular and genetic tools of C. elegans including the ability to monitor sperm migration in vivo through its transparent body, make it an outstanding model system for fundamental research. Furthermore, the unique biology of its spermatogenesis program provides a novel context for exploring the function of kinases and phosphatases, largely in the absence of new gene transcription. OBJECTIVES: The proposed studies will explore the functions of a kinase SPE-6 and a pseudophosphatase SPE-54 whose phenotypic defects provide an entry point for investigating largely unexplored cellular and developmental pathways as such analysis often generates transformative insights in biology. First, we will investigate the molecular mechanisms by which SPE-6 regulates three distinct cellular pathways: a) assembly of a nematode specific cytoskeletal protein into tightly packed fibrous bodies, b) detachment of spermatocytes from the germline syncytium, and c) the remodeling of chromosomes so that they can be segregated during the meiotic divisions. Secondly, we will use both in vivo and in vitro approaches to investigate how SPE-54 regulates the directed mobility of the sperm to the site of fertilization. The findings should broadly inform our understanding of kinase and pseudophosphatase functions in diverse cell types.

相关性：在正常和病理条件下，激酶和磷酸酶是 细胞和发育途径的关键翻译后调节剂。错误调节 这些酶与从阿尔茨海默氏症和癌症到不孕症的各种病理相关。 我们的研究将研究与阿尔茨海默氏症相关激酶有关的激酶SPE-6（TAU 微管蛋白激酶和伪磷酸酶SPE-54，一种临界作用的酶 直到最近才被认可。理由：我们的研究将研究这些功能 在秀丽隐杆线虫精子发育和精子功能的独特背景下的蛋白质。因为 人类和秀丽隐杆线虫共享许多相同的基因，在秀丽隐杆线虫中发现的发现可以是 与人类直接相关。相反，生育需要的线虫特异性蛋白质是 有希望的药物靶标，用于消毒数十亿人口的线虫寄生虫。作为 实验系统，秀丽隐杆线虫的分子和遗传工具，包括 监测精子通过其透明体内的体内迁移，使其成为出色的模型 基础研究系统。此外，其精子发生的独特生物学 程序提供了一种新颖的背景，用于探索激酶和磷酸酶的功能， 在很大程度上没有新基因转录的情况下。目标：拟议的研究将 探索激酶SPE-6和伪磷酸酶SPE-54的功能，其表型 缺陷为研究大量未开发的细胞和发育提供了一个切入点 这样的途径这种分析通常会产生生物学上的变革性见解。首先，我们会的 研究SPE-6调节三种不同细胞的分子机制 途径：a）线虫特异性细胞骨架蛋白的组装成紧密纤维 身体，b）脱离种系合胞质的精子细胞，c）重塑 染色体以便在减数分裂分裂期间可以分离它们。其次，我们会的 使用体内和体外方法研究SPE-54如何调节定向 精子向受精部位的迁移。这些发现应该广泛地告知我们 了解各种细胞类型中激酶和伪磷酸酶的功能。