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:10268218
- 负责人:
- 金额:$ 32.45万
- 依托单位:
- 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:
- 关键词:AffectAutophagocytosisBindingCell Culture TechniquesCell CycleCell modelCellsChIP-seqChromosomesContraceptive methodsDataDiploidyEventGatekeepingGene ActivationGenesGeneticGerm CellsHaploidyIn VitroIndividualInvestigationKnowledgeLinkLoxP-flanked alleleLysosomesMale Contraceptive AgentsMale InfertilityMammalsMediatingMeiosisMeiotic Prophase IMitoticMolecularMusOrganellesPathway interactionsPharmacologyPhenotypeProcessProductionProteinsProteomicsRecyclingReproductive MedicineResearchResearch PersonnelResistanceRoleSpermatocytesSpermatogenesisSpermatogenic CellSpermatogoniaSystemTechniquesTestingTimeTransactivationTranslationsTretinoinWorkZinc Fingersbasegenetic approachhomologous recombinationin vivoinhibition of autophagyinhibitor/antagonistlead candidatemale fertilitymenmutantnew therapeutic targetnovelnovel strategiesoverexpressionpreventpromoterprotein degradationreceptorsmall hairpin RNAsperm celltranscription 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
精子数量和质量差是男性不育的主要原因,全世界约7%的男性受到影响。男性生育能力
取决于二倍体生殖细胞(精原细胞)转化为单倍体精子(精子)。减数分裂
在这一过程中,启动是一个决定性的步骤,围绕着从有丝分裂到减数分裂的细胞周期的转变,以及
需要激活减数分裂前期I的染色体事件所需的减数分裂基因到目前为止,最好的
哺乳动物减数分裂启动的特征守门人是由维甲酸基因8(Stra8)刺激的,因为
Stra8P-/-P生殖细胞不表达减数分裂基因的一个子集,不进入减数分裂。我们最近的研究表明
STRA8作为自噬抑制因子的一个新的分子作用,表明减数分裂起始之间存在新的联系
以及自噬,这是一个蛋白质和细胞器的降解过程。根据这一信息,我们假设
STRA8介导的自噬抑制允许减数分裂基因所需蛋白质的积累
激活和启动;在没有STRA8的情况下,这些蛋白质通过自噬降解,从而阻止减数分裂。
为了验证我们的假设,我们将:1)研究自噬在STRA8介导的减数分裂启动中的作用。2)
定义自噬和减数分裂启动之间的分子联系。我们的研究将共同建立自噬
作为一种尚未被认识的减数分裂启动调节器,并发现自噬敏感蛋白作为
哺乳动物在这一过程中的基本分子步骤。通过更好地理解自噬
作为减数分裂诱导的障碍,我们的研究将为体外配子的研究提供重大的技术进步。
制作。最终,我们研究的翻译可能在自噬途径中识别新的治疗靶点。
用于男性不育症或避孕治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ning Wang其他文献
Ning Wang的其他文献
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{{ truncateString('Ning Wang', 18)}}的其他基金
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
- 批准号:
10437882 - 财政年份:2020
- 资助金额:
$ 32.45万 - 项目类别:
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
- 批准号:
10556093 - 财政年份:2020
- 资助金额:
$ 32.45万 - 项目类别:
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
- 批准号:
10711993 - 财政年份:2020
- 资助金额:
$ 32.45万 - 项目类别:
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
- 批准号:
10101173 - 财政年份:2020
- 资助金额:
$ 32.45万 - 项目类别:
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
- 批准号:
10652466 - 财政年份:2020
- 资助金额:
$ 32.45万 - 项目类别:
Aging and Ovarian Stem Cell Niche Dysfunction
衰老与卵巢干细胞生态位功能障碍
- 批准号:
8732113 - 财政年份:2013
- 资助金额:
$ 32.45万 - 项目类别:
Aging and Ovarian Stem Cell Niche Dysfunction
衰老与卵巢干细胞生态位功能障碍
- 批准号:
8738557 - 财政年份:2013
- 资助金额:
$ 32.45万 - 项目类别:
Aging and Ovarian Stem Cell Niche Dysfunction
衰老与卵巢干细胞生态位功能障碍
- 批准号:
8316123 - 财政年份:2011
- 资助金额:
$ 32.45万 - 项目类别:
Aging and Ovarian Stem Cell Niche Dysfunction
衰老与卵巢干细胞生态位功能障碍
- 批准号:
8190097 - 财政年份:2011
- 资助金额:
$ 32.45万 - 项目类别:
Bioengineering approaches to map mechanotransduction in the living cell
绘制活细胞中机械转导的生物工程方法
- 批准号:
10359167 - 财政年份:2005
- 资助金额:
$ 32.45万 - 项目类别: