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

• 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
• 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' 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' 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

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.

抽象的 与她们的整体寿命相比，女性的生育窗口很短。生育力通常达到顶峰 25 岁左右，但随后卵母细胞质量和卵母细胞数量的损失导致生殖能力下降 随后在 51 岁左右进入更年期。随着女性越来越推迟，这成为一个健康问题 生育直至超过“高龄产妇”(AMA)（即 35 岁以上）。 AMA 女性面临以下风险 非整倍体增加，导致流产、出生缺陷、早产和其他高风险妊娠。 这主要是由于接受人工生殖技术的女性卵母细胞质量缺陷造成的 使用年轻的捐赠卵子在所有年龄段的怀孕率相似。虽然定义不明确，但卵母细胞质量下降 可归因于多种因素，包括染色体结构缺陷、蛋白质稳态和线粒体， 但卵母细胞质量随着时间的推移而丧失的大部分原因尚不清楚。我们最近产生了一种新的卵母细胞特异性 翻译后修饰 (PTM) 所需的中心酶 (UBA3) 的条件敲除 (ocKO)， neddylation。 Neddylation 将小泛素样蛋白 NEDD8 通过共价键连接到靶蛋白上 E1-E2-E3 酶级联调节蛋白质结构、功能、稳定性和亚细胞定位。这 neddylation 在卵泡发生过程中女性生育力和卵母细胞发育中的作用尚不清楚。我们的 初步数据表明，Uba3 ocKO 雌性小鼠是不育的，显示出大多数卵母细胞在年轻时被耗​​尽 成年期，卵母细胞染色体结构、减数分裂恢复和线粒体发生变化 活动，表明卵母细胞质量下降。由于neddylation调节线粒体结构和功能 一些细胞，线粒体功能被认为是卵母细胞质量的关键驱动因素，我们的中心假设是 卵泡发生过程中卵母细胞的发育需要neddylation，部分是通过调节 线粒体功能。该项目的目标旨在 (1) 确定 neddylation 损失如何改变 卵母细胞中的线粒体功能和（2）表明 neddylation 活性随着卵母细胞的老化而下降。这 这些目标的结果将首次表明 neddylation 与线粒体功能障碍有关 卵母细胞的变化以及 neddylation 效率的变化可能会驱动卵母细胞衰老的各个方面。此外，这些研究 将构成未来研究的基础，以确定是否可以在 ART 环境中利用 neddylation 作为提高老年女性卵子质量的一种手段。