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Role of Ptchd3 in Spermatogenesis

Ptchd3 在精子发生中的作用

基本信息

批准号：
7778954
负责人：
GUO-ZHANG ZHU
金额：
$ 21.28万
依托单位：
MARSHALL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-18 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778954
关键词：
Binding Biochemical Biochemical Genetics Biological Assay Cells Data Defect Development Developmental Process Disease Ectopic Expression Education Erinaceidae Family Family member Genes Genetic Germ Cells Goals Human Immunohistochemistry Infertility Institution Knock-out Knowledge Laboratories Lead Ligands Literature Male Contraceptions Mediating Membrane Molecular Mus Mutant Strains Mice One-Step dentin bonding system Organism Play Process Proliferating Proteins Regulation Reporting Reproduction Research Role Scholarship Signal Pathway Signal Transduction Spermatocytes Spermatogenesis Spermatogenic Cell Staging Sterility Students Testing Testis Vertebrates Work Zebrafish base insight male member men mouse model novel null mutation protein expression public health relevance receptor research study sertoli cell smoothened signaling pathway sperm cell

项目摘要

DESCRIPTION (provided by applicant): The evolutionarily conserved Hedgehog (Hh) signaling pathway plays a crucial role in many developmental and disease processes. Hh, secreted protein ligand, initiates a signaling cascade in the receiving cell through binding to its membrane receptor Patched. Ptchd3 has been recently identified as a male germ cell-specific gene in our laboratory and is conserved among many organisms, including human, mouse and zebrafish. It contains a conserved Patched domain and is predicted to have Hh receptor activity. In vertebrates, there are three members of the Hh family, Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dhh). Dhh is the only Hh family member that is expressed in testis, specifically, in Sertoli cells. Previous studies have demonstrated that Dhh is essential for spermatogenesis---a highly ordered, precisely orchestrated developmental process in which male germ cells proliferate and differentiate to produce sperm. The molecular mechanism of Dhh function during spermatogenesis, however, is unknown. In this application, we propose to test the hypothesis that Ptchd3 is a novel Dhh receptor on male germ cells and mediates Dhh effect on spermatogenesis. Two specific aims will be carried out to test our hypothesis. In Aim 1, we will investigate if Ptchd3 is a component of Dhh signaling in spermatogenic cells by a broad spectrum of assays, including biochemical, genetic, pharmacological, molecular and cellular approaches. In Aim 2, we will determine if Ptchd3 is required for spermatogenesis by using Ptchd3 null mutant mice. These studies constitute one step toward attainment of our long-term research goal- --understanding the molecular and cellular mechanisms of mammalian reproduction. Results from these studies will advance our knowledge about the regulation of spermatogenesis, may provide insight into unexplained (or idiopathic) infertility in men, and may lead to new strategies for male contraception. PUBLIC HEALTH RELEVANCE: Results from these studies will advance our knowledge about the regulation of spermatogenesis, may provide insight into unexplained (or idiopathic) infertility in men, and may lead to new strategies for male contraception.

描述(由申请人提供)：进化上保守的Hedgehog(HH)信号通路在许多发育和疾病过程中起着至关重要的作用。HH是一种分泌型蛋白配体，通过与其补丁的膜受体结合，在受体细胞中启动信号级联反应。Ptchd3基因是本实验室最近发现的一种雄性生殖细胞特异性基因，在包括人类、小鼠和斑马鱼在内的许多生物中都是保守的。它含有一个保守的补丁结构域，并被预测具有HH受体活性。在脊椎动物中，HH家族有三个成员，Sonic Hedgehog(Shh)，印度刺猬(IHH)和沙漠刺猬(DHH)。DHH是唯一在睾丸中表达的HH家族成员，尤其是在支持细胞中表达。之前的研究已经证明，DHH对精子发生是必不可少的-这是一种高度有序的、精确安排的发育过程，在这个过程中，男性生殖细胞增殖和分化产生精子。然而，DHH在精子发生过程中发挥作用的分子机制尚不清楚。在这一应用中，我们建议检验Ptchd3是一种新的男性生殖细胞上的DHH受体的假设，并介导DHH在精子发生中的作用。我们将实现两个具体目标来检验我们的假设。在目标1中，我们将通过包括生化、遗传学、药理学、分子和细胞方法在内的广泛分析来研究Ptchd3是否是生精细胞中DHH信号的组成部分。在目标2中，我们将通过使用Ptchd3缺失突变小鼠来确定Ptchd3是否是精子发生所必需的。这些研究是朝着实现我们的长期研究目标-了解哺乳动物繁殖的分子和细胞机制--迈出的一步。这些研究的结果将促进我们对精子发生调节的了解，可能为男性不明原因(或特发性)不育症提供洞察，并可能导致新的男性避孕策略。公共卫生相关性：这些研究的结果将促进我们对精子发生调节的了解，可能为男性不明原因(或特发性)不育症提供洞察，并可能导致新的男性避孕策略。