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：
10101173
负责人：
Ning Wang
金额：
$ 33.11万
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/10101173
关键词：
Affect 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 Pharmacology Phenotype Process Production Proteins Proteomics Recycling Reproductive Medicine Research Research Personnel Resistance Role Spermatogenesis Spermatogenic Cell Spermatogonia System Techniques Testing Time Transactivation Translations Tretinoin Work Zinc Fingers base genetic approach homologous recombination in vivo inhibition of autophagy inhibitor/antagonist lead candidate male male fertility men mutant new therapeutic target novel novel strategies overexpression prevent promoter protein degradation 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.

项目摘要精子数量和质量差是男性不育症的主要原因，影响了全世界约7％的男性。男性生育能力取决于二倍体生殖细胞（精子）转化为单倍体精子（精子）。减数分裂启动是此过程中的决定性步骤，围绕从有丝分裂到减数分裂细胞周期的过渡和需要激活减数分裂预言的染色体事件。视黄酸基因8（stra8）刺激了哺乳动物中减数分裂起始的特征，这是 Stra8p - / - P生殖细胞无法表达减数分裂基因的子集，并且不进入减数分裂。我们最近的工作表明 Stra8作为自噬的抑制剂的一种新型分子作用，暗示了减数分裂启动之间的新联系和自噬，一种蛋白质和细胞细胞器降解过程。基于这些信息，我们假设 stra8介导的自噬抑制允许积累减数分裂基因所需的蛋白质激活和主动性；在没有Stra8的情况下，这些蛋白质被自噬，排除减数分裂而降解。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。 2）定义自噬和减数分裂起始之间的分子联系。一起，我们的研究将建立自噬作为减数分裂起始和发现自噬敏感蛋白的尚未认可的调节剂在此过程中，基本的分子步骤在哺乳动物中。通过更好地了解自噬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生产。最终，我们研究的翻译可以识别自噬途径中的新型治疗靶标用于男性不育症或避孕治疗。