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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.

项目总结