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: 10509284
• 负责人: STEPHANIE A. PANGAS
• 金额: $ 24万
• 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/10509284
• 关键词: Age; Aging; Alzheimer' s Disease; Aneuploidy; Automobile Driving; Biology; Biosensor; Catalytic Domain; Cell Aging; Cell physiology; Cells; Chemicals; Chromosome Structures; Chromosomes; 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; Longevity; 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; 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; Suggestion; System; Technology; Time; Tomogram; Ubiquitin Like Proteins; Vision; Woman; Women' s Health; advanced maternal age; base; chronic liver disease; 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 function; proteostasis; recruit; reproductive; reproductive senescence; 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.

摘要 与女性的整体寿命相比，女性的生殖窗口很短。生育率通常达到峰值 大约25岁，但随后的卵母细胞质量和卵子数量的丧失会导致生殖能力下降 然后是51岁左右的更年期。随着女性越来越多地推迟，这成为了一个健康问题 生育至超过“高龄产妇年龄”(即35岁以上)。美国医学会女性面临患上 导致流产、出生缺陷、早产和其他高危妊娠的非整倍体增加。 这主要是由于接受人工生殖技术的妇女卵母细胞质量的缺陷造成的。 使用年轻的捐赠者卵子在所有年龄段都有相似的怀孕率。虽然定义不明确，但卵母细胞质量下降 可以归因于几个因素，包括染色体结构缺陷，蛋白质平衡和线粒体， 但是，卵母细胞质量在很大程度上会随着时间的推移而丧失，目前尚不清楚。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(OKKO)， 这是一件很糟糕的事。Neddyling通过一种新的方式将类泛素小蛋白NEDD8共价连接到靶蛋白上。 调节蛋白质结构、功能、稳定性和亚细胞定位的酶的级联反应。这个 在卵泡发生过程中，排卵在女性生育和卵母细胞发育中的作用尚不清楚。我们的 初步数据显示，Uba3 Ocko雌性小鼠是不育的，表明大多数卵母细胞被幼鼠耗尽 成年后，卵母细胞的染色体结构发生变化，减数分裂恢复，线粒体 活性，暗示卵母细胞质量下降。AS脱氧核糖核酸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 卵泡形成过程中卵母细胞的发育需要核化，这部分是通过调节 线粒体功能。该项目的目的是：(1)确定糖尿病的损失如何改变 线粒体在卵母细胞中的功能和(2)表明随着卵母细胞的老化，线粒体的活性下降。这个 这些目标的结果将首次表明，糖尿病与线粒体功能障碍有关。 卵母细胞和核化效率的变化可能推动卵母细胞老化的各个方面。此外，这些研究 将为未来的研究奠定基础，以确定是否可以在艺术环境中利用新陈代谢 作为提高老年妇女卵子中卵母细胞质量的一种手段。