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A functional neddylation pathway underlies oocyte quality and aging

功能性neddylation途径是卵母细胞质量和衰老的基础

基本信息

批准号：
10672284
负责人：
STEPHANIE A. PANGAS
金额：
$ 20万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10672284
关键词：
Age Aging Alzheimer&apos s Disease Aneuploidy Automobile Driving Biology Biosensor Catalytic Domain Cell Aging Cell physiology Cells Chemicals Chromosome Structures Chromosomes Chronic Disease Complement Complex Congenital Abnormality Cryo-electron tomography Data Defect Delayed Childbearing Development Diagnostic Disease Enzymes Female Female infertility Fertility Fluorescence Foundations Functional disorder Future Genus Hippocampus Glycolysis Goals Gynecology Health Heart Diseases High-Risk Pregnancy Knockout Mice Link Liver diseases Longevity LoxP-flanked allele Malignant Neoplasms Meiosis Menopause Mitochondria Molecular Monitor Morphology Mus National Institute of Child Health and Human Development Oocytes Organelles Ovarian Follicle Pathway interactions Phenotype Post-Translational Protein Processing Postmenopause Pregnancy Rate Premature Birth Primordial Follicle Process Proteins Regulation Reproductive Health Reproductive Technology Research Resources Respiration Risk Role Specialist Spontaneous abortion Sterility Strategic Planning Structure System Technology Time Tomogram Ubiquitin Like Proteins Vision Woman Women&apos s Health advanced maternal age conditional knockout design egg emerging adult female fertility folliculogenesis inhibitor mitochondrial dysfunction molecular array mouse model neuronal cell body novel older women oocyte quality pregnant protein structure proteostasis recruit reproductive time use trafficking young adult

项目摘要

ABSTRACT Women have a short reproductive window compared to their overall lifespan. Fertility usually peaks around age 25, but a subsequent loss of oocyte quality and oocyte numbers leads to reproductive decline followed by menopause around age 51. This becomes a health concern as women increasingly delay childbearing until they are past ‘advanced maternal age’ (AMA) (i.e., ages 35+). AMA women are at risk of increased aneuploidy that leads to miscarriage, birth defects, premature birth and other high-risk pregnancies. This is primarily driven by defects in oocyte quality, as women undergoing artificial reproductive technologies using young donor eggs have similar pregnancy rates at all ages. While poorly defined, declines in oocyte quality can be attributed to several factors, including defective chromosome structure, proteostasis, and mitochondria, but much of why oocyte quality is lost overtime is unknown. We recently generated a novel oocyte-specific conditional knockout (ocKO) for a central enzyme (UBA3) required for the post-translational modification (PTM), neddylation. Neddylation covalently attaches the small ubiquitin-like protein, NEDD8, to target proteins via an E1-E2-E3 enzymatic cascade to regulate protein structure, function, stability, and subcellular localization. The role of neddylation in female fertility and oocyte development during folliculogenesis is not known. Our preliminary data show that Uba3 ocKO female mice are sterile, show depletion of most oocytes by young adulthood, and have oocytes with changes in chromosome structure, meiotic resumption, and mitochondrial activity, suggestive of a loss in oocyte quality. As neddylation regulates mitochondrial structure and function in some cells, and mitochondrial function is thought to be a key driver of oocyte quality, our central hypothesis is that neddylation is required for the development of oocytes during folliculogensis in part by regulating mitochondrial function. The Aims of this project are designed to (1) determine how loss of neddylation alters mitochondrial function in oocytes and (2) demonstrate that neddylation activity declines with oocyte aging. The results from these Aims will show for the first time that neddylation is linked to mitochondrial dysfunction in oocytes and that changes in neddylation efficiency may drive aspects of oocyte aging. In addition, these studies will form the foundation of future studies to determine whether neddylation could be exploited in the ART setting as a means to increase oocyte quality in eggs of older women.

摘要