Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

通过自噬途径定义减数分裂起始机制

基本信息

批准号：
10652466
负责人：
Ning Wang
金额：
$ 32.66万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652466
关键词：
Affect Alleles Autophagocytosis Binding Cell Culture Techniques Cell Cycle Cell model Cells ChIP-seq Chromosomes Contraceptive methods Data Diploidy Event Gatekeeping Gene Activation Genes Genetic Germ Cells Haploidy In Vitro Individual Investigation Knowledge Link LoxP-flanked allele Lysosomes Male Contraceptive Agents Male Infertility Mammals Mediating Meiosis Meiotic Prophase I Mitotic Molecular Mus Organelles Pathway interactions Phenotype Process Production Protein Degradation Induction Proteins Proteomics Recycling Reproductive Medicine Research Research Personnel Resistance Role Spermatocytes Spermatogenesis Spermatogenic Cell Spermatogonia System Techniques Testing Time Transactivation Translations Tretinoin Work Zinc Fingers genetic approach homologous recombination in vivo inhibition of autophagy inhibitor lead candidate male fertility men mutant new therapeutic target novel novel therapeutic intervention overexpression pharmacologic prevent promoter receptor small hairpin RNA sperm cell transcription factor

项目摘要

PROJECT SUMMARY Poor sperm quantity and quality are major causes of male infertility, affecting ~7% of men worldwide. Male fertility depends on the conversion of diploid germ cells (spermatogonia) into haploid spermatozoa (sperm). Meiotic initiation, a defining step in this process, revolves around the transition from mitotic to meiotic cell cycles and entails activation of meiotic genes required for the chromosomal events of meiosis prophase I. To date, a best characterized gatekeeper of meiotic initiation in mammals is stimulated by retinoic acid gene 8 (Stra8), in that Stra8P–/–P germ cells fail to express a subset of meiotic genes and do not enter meiosis. Our recent work indicates a novel molecular role of STRA8 as a suppressor of autophagy, suggesting a novel link between meiotic initiation and autophagy, a protein and cellular organelle degradation process. Based on this information, we hypothesize that STRA8-mediated suppression of autophagy allows accumulation of proteins required for meiotic gene activation and initiation; in the absence of STRA8, these proteins are degraded by autophagy, precluding meiosis. To test our hypothesis, we will: 1) investigate the role of autophagy in STRA8-mediated meiotic initiation. 2) define the molecular links between autophagy and meiotic initiation. Together, our study will establish autophagy as a yet unrecognized regulator of meiotic initiation and uncover autophagy-sensitive proteins that serve as essential molecular steps during this process in mammals. By developing a better understanding of autophagy as a barrier to meiotic induction, our study will offer a significant technical advancement for in vitro gamete production. Ultimately, translation of our study may identify novel therapeutic targets in the autophagy pathway for male infertility or contraception treatment.

项目概要精子数量和质量差是男性不育的主要原因，影响全球约 7% 的男性生育能力。取决于二倍体生殖细胞（精原细胞）向单倍体精子（减数分裂）的转化。启动是该过程中的一个决定性步骤，围绕着从有丝分裂到减数分裂细胞周期的转变，需要激活减数分裂前期 I 染色体事件所需的减数分裂基因。迄今为止，最好的方法是哺乳动物减数分裂起始的特征性看门人是由视黄酸基因 8 (Stra8) 刺激的，因为 Stra8P–/–P 生殖细胞无法表达减数分裂基因的子集，并且不会进入减数分裂。 STRA8 作为自噬抑制剂的新分子作用，表明减数分裂起始之间存在新的联系和自噬，一种蛋白质和细胞器的降解过程，基于这些信息，我们勇敢地进行了研究。 STRA8介导的自噬抑制使得减数分裂基因所需的蛋白质积累激活和启动；在缺乏 STRA8 的情况下，这些蛋白质会被自噬降解，从而阻止减数分裂。为了检验我们的假设，我们将：1) 研究自噬在 STRA8 介导的减数分裂起始中的作用。我们的研究将共同定义自噬和减数分裂起始之间的分子联系。作为减数分裂起始的尚未识别的调节因子，并发现自噬敏感蛋白通过更好地了解自噬，了解哺乳动物这一过程中的重要分子步骤。作为减数分裂诱导的障碍，我们的研究将为体外配子提供重大的技术进步最终，我们研究的转化可能会确定自噬途径中的新治疗靶点。用于男性不育或避孕治疗。