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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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，激酶和磷酸酶都是细胞和发育途径的关键翻译后调节因子。监管不当这些酶与从阿尔茨海默病、癌症到不孕不育等多种病症有关。我们的研究将调查与阿尔茨海默病相关激酶 (tau) 相关的激酶 SPE-6 微管蛋白激酶和假磷酸酶 SPE-54，一类酶，其关键作用是最近才被认可。理由：我们的研究将调查这些的功能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。因为人类和线虫有许多相同的基因，线虫中的发现可以与人类直接相关。相反，生育所需的线虫特异性蛋白质是有前景的药物靶标可用于消灭感染超过十亿人的线虫寄生虫。作为一个实验系统，线虫的分子和遗传工具，包括能够通过透明体监测精子在体内的迁移情况，使其成为杰出的模型基础研究体系。此外，其精子发生的独特生物学程序为探索激酶和磷酸酶的功能提供了新的背景，很大程度上是在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 和假磷酸酶 SPE-54 的功能，其表型缺陷为研究很大程度上未开发的细胞和发育提供了一个切入点此类分析通常会产生生物学领域的变革性见解。首先，我们将研究 SPE-6 调节三种不同细胞的分子机制途径：a) 将线虫特异性细胞骨架蛋白组装成紧密堆积的纤维状体，b）精母细胞与种系合胞体的分离，以及c）重塑染色体，以便它们可以在减数分裂期间分离。其次，我们将使用体内和体外方法来研究 SPE-54 如何调节定向精子移动到受精部位的能力。研究结果应该广泛地告知我们了解不同细胞类型中激酶和假磷酸酶的功能。