Protein Sumoylation in OOCYTE Development

卵细胞发育中的蛋白质苏酰化

基本信息

批准号：
9247323
负责人：
STEPHANIE A. PANGAS
金额：
$ 32.89万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247323
关键词：
Affect Age Age-Months Aneuploidy Birth CRISPR/Cas technology Candidate Disease Gene Cell physiology Cessation of life Chromosome abnormality Chromosomes Computer Simulation Congenital Abnormality DNA Binding Data Defect Development Diagnostic Disease Embryo Embryonic Development Enterobacteria phage P1 Cre recombinase Enzymes Feedback Female Female sterility Fertility Gene Deletion Gene Expression Gene Targeting General Population Generations Genetic Transcription Genotype Germ Cells Goals Growing Follicle Growth Differentiation Factor 9 Health Heart Diseases Homeobox Genes Hot flushes Human In Vitro Infertility Knock-out Lead Longevity Mediating Meiosis Menopause Mus Mutate Mutation Newborn Infant Oocytes Ovarian Ovarian Follicle Ovary Pathway interactions Phenotype Post-Translational Protein Processing Pregnancy loss Premature Menopause Premature Ovarian Failure Primordial Follicle Process Proteins Proteome Proteomics Puberty Regulation Reproductive Technology Resources Role Secondary to Site Sterility Testing Vision Woman Women&apos s Health bone loss design early experience egg folliculogenesis genome editing implantation in vivo insight intraovarian male mouse model negative affect novel oocyte maturation postnatal premature primary ovarian insufficiency protein function reproductive segregation tool transcription factor transcriptome sequencing transcriptomics young adult

项目摘要

ABSTRACT Reproductive lifespan in women spans puberty to the menopause. However, in about 1-2% of women, early menopause occurs, and this has negative health consequences, including increases in heart disease, bone loss, hot flashes, or even early death. The number of oocytes found in the non-growing pool of ovarian follicles (the "ovarian reserve"), is currently thought to largely determine the age at the menopause. Thus, premature menopause arises if oocytes are dysfunctional or damaged. Mouse models demonstrate that oocyte-specific transcription factors are required for the development of oocytes within the ovarian reserve. Deletion of these genes, which includes newborn ovary homeobox gene (Nobox), causes female sterility and premature loss of oocytes in mice. Furthermore, women with premature ovarian failure frequently have mutations in NOBOX. Even though NOBOX is required for oocyte development, there is little to no information on how NOBOX function is regulated. In silico analysis of NOBOX identified SUMOylation as a potential regulatory mechanism. SUMOylation is a posttranslational modification that controls protein stability, localization, and activity, particularly for transcription factors. However, the function of SUMOylation during intraovarian oocyte development is not known. Therefore, we generated a novel oocyte-specific knockout of Ubc9, which is a central component of the SUMOylation cascade. Loss of Ubc9 in oocytes beginning at the primordial follicle stage caused female sterility and a full depletion of the oocyte reserve in young adult mice. Preliminary data indicate that loss of SUMOylation affects NOBOX function and the phenotype manifests at the primary to secondary follicle stage. The Aims of this project designed to (1) determine why there are defects in oocyte development at the primary to secondary follicle stage and (2) elucidate how SUMOylation alters oocyte- specific transcription factor function, resulting in altered gene expression and oocyte death/survival. The results from these Aims will provide insight into the regulation of key oocyte-specific transcription factors and the genesis of premature ovarian failure. Importantly, these studies will establish SUMOylation as an essential process in intraovarian oocyte development.

抽象的女性的生殖寿命跨越青春期至更年期。然而，大约 1-2% 的女性在早期更年期发生，这会对健康产生负面影响，包括心脏病、骨骼疾病的增加丧失、潮热，甚至早逝。在非生长卵泡池中发现的卵母细胞数量（“卵巢储备功能”）目前被认为在很大程度上决定了绝经年龄。因此，过早如果卵母细胞功能失调或受损，就会出现更年期。小鼠模型证明卵母细胞特异性卵巢储备中卵母细胞的发育需要转录因子。删除这些基因，其中包括新生卵巢同源框基因（Nobox），会导致女性不育和过早丧失性能力。小鼠的卵母细胞。此外，卵巢早衰的女性经常出现 NOBOX 突变。尽管卵母细胞发育需要 NOBOX，但关于 NOBOX 如何发挥作用的信息却很少甚至没有。功能受到调节。 NOBOX 的计算机分析确定 SUMO 化是一种潜在的调节机制。 SUMOylation 是一种控制蛋白质稳定性、定位和活性的翻译后修饰，特别是对于转录因子。然而，SUMO化在卵巢内卵母细胞过程中的功能发展情况不得而知。因此，我们产生了一种新型的 Ubc9 卵母细胞特异性敲除方法，这是一种 SUMOylation 级联的核心组成部分。卵母细胞中 Ubc9 从原始卵泡开始丢失该阶段导致雌性不育，并导致年轻成年小鼠的卵母细胞储备完全耗尽。初步数据表明 SUMO 化的丧失会影响 NOBOX 功能，并且表型表现在初级到次级卵泡阶段。该项目的目的旨在 (1) 确定卵母细胞存在缺陷的原因 (2) 阐明 SUMOylation 如何改变卵母细胞特定转录因子功能，导致基因表达改变和卵母细胞死亡/存活。结果这些目标将深入了解关键卵母细胞特异性转录因子的调节以及卵巢早衰的成因。重要的是，这些研究将确立 SUMOylation 是一种重要的卵巢内卵母细胞发育过程。