Regulation of C. elegans Sperm Differentiation

线虫精子分化的调节

• 批准号: 7677265
• 负责人: Gillian Stanfield
• 金额: $ 28.6万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677265
• 关键词: Address; Alleles; Animals; Behavior; Biochemical; Biological Assay; Biological Models; Biological Phenomena; Biological Process; Caenorhabditis elegans; Cell Polarity; Cell surface; Cells; Cellular Morphology; Complement; Development; Developmental Process; Disease; Ensure; Environment; Enzymes; Family; Flagella; Genes; Genetic; Genetic Epistasis; Genetic Screening; Goals; Human; In Vitro; Malignant Neoplasms; Mediating; Modeling; Molecular; Morphogenesis; Morphology; Mutation; Nematoda; Neoplasm Metastasis; Pathway interactions; Peptide Hydrolases; Physiological Processes; Process; Protease Inhibitor; Proteins; Proteolysis; RNA Interference; Regulation; Research; Serine Protease; Signal Transduction; Spermatids; Spermiogenesis; Surveys; System; Testing; Tissues; Trypsin; Trypsin Inhibitors; Work; Wound Healing; cancer cell; cell motility; design; extracellular; gain of function; gastrulation; in vitro Assay; in vivo; inhibitor/antagonist; insight; loss of function; male; mutant; novel; progenitor; public health relevance; research study; sperm cell; therapeutic target; trypsin-like serine protease

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand how extracellular signals trigger cells to differentiate into a polarized, motile state. Whereas cellular motility is required for normal biological processes such as morphogenesis and wound healing, motility also contributes to cancer metastasis. Therefore it is important that the acquisition of motility be tightly regulated. The differentiation of C. elegans sperm provides a model system for studying this regulation. Like other migratory cells, these sperm move by crawling, and their maturation - termed sperm activation -- involves a transformation from a symmetrical, immotile spermatid to a highly polarized, motile spermatozoon capable of directional motility. While genetic studies have shown that sperm activation is subject to controls that differ between males and hermaphrodites, and a variety of compounds have been identified that can activate sperm in vitro, no in vivo activation trigger has been identified. This proposal is designed to test the hypothesis that one such trigger may involve proteolysis. Our preliminary studies have identified a protease inhibitor, SWM-1, and serine protease, TRY-5, that appear to function antagonistically to regulate sperm activation in males. To extend these observations, our specific aims are to (1) determine in which contexts try-5 function is required for sperm activation and how its activity is coordinated among different tissues; (2) determine whether SWM-1/TRY-5 can function as a protease-inhibitor system to regulate sperm activation in in vitro assays, and test candidate targets for try-5-dependent cleavage in vivo; and (3) identify additional factors that promote sperm activation downstream of swm-1. These studies will provide insight into two widely important biological phenomena: the regulation of cellular motility and protease-mediated signaling. Furthermore, since proteases are important therapeutic targets for cancer and other diseases, this work may be applicable to the development of novel inhibitors. PUBLIC HEALTH RELEVANCE: The acquisition of a polarized, migratory cellular morphology is crucial for the normal processes of development and wound healing, and also contributes to the abnormal transition to metastasis in cancer cells. C. elegans sperm differentiation provides a model system for studying the signals that trigger the transition of cells to a migratory morphology. We are using C. elegans to study one such signal that is mediated by proteases, an important family of enzymes that is present in all animals and in humans.

描述(申请人提供)：这项研究的长期目标是了解细胞外信号如何触发细胞分化为极化的、可运动的状态。虽然细胞运动是形态形成和伤口愈合等正常生物学过程所必需的，但运动也有助于癌症转移。因此，对运动性的获得进行严格监管是很重要的。线虫精子的分化为研究这一调控提供了一个模型系统。像其他迁移细胞一样，这些精子通过爬行移动，它们的成熟--称为精子激活--涉及从对称的、静止的精子细胞到高度极化的、能够定向运动的精子的转变。虽然遗传学研究表明，精子激活受到男性和两性人不同的控制，而且已经确定了多种化合物可以在体外激活精子，但尚未发现体内激活触发因素。这一提议旨在检验这样一种假设，即其中一个触发因素可能涉及蛋白质分解。我们的初步研究已经确定了一种蛋白酶抑制剂SWM-1和丝氨酸蛋白酶Try-5，它们似乎具有拮抗地调节男性精子激活的功能。为了扩大这些观察，我们的具体目标是：(1)确定精子激活所需的Try-5功能及其在不同组织中如何协调；(2)确定SWM-1/Try-5是否可以作为蛋白酶抑制系统在体外调节精子激活，并测试依赖于Try-5的体内切割候选靶点；以及(3)确定在swm-1下游促进精子激活的其他因素。这些研究将提供对两个广泛重要的生物学现象的洞察：细胞运动的调节和蛋白酶介导的信号传递。此外，由于蛋白酶是癌症和其他疾病的重要治疗靶点，这项工作可能适用于新型抑制剂的开发。公共卫生相关性：获得极化的、迁移的细胞形态对于正常的发育和伤口愈合过程至关重要，也有助于癌细胞向转移的异常转变。线虫的精子分化为研究触发细胞向迁移形态转变的信号提供了一个模型系统。我们正在使用线虫来研究由蛋白酶介导的一个这样的信号，蛋白酶是一个重要的酶家族，存在于所有动物和人类中。