Grem1 and Grem2 in embryonic ovary development

Grem1 和 Grem2 在胚胎卵巢发育中的作用

基本信息

批准号：
10584129
负责人：
STEPHANIE A. PANGAS
金额：
$ 32万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584129
关键词：
Adult Affect Aneuploidy Apoptosis Architecture Binding Proteins Birth Bone Morphogenetic Proteins Cell Count Cell Death Cell Differentiation process Cells Data Defect Development Disease Embryo Embryonic Development Family Feedback Female Fertility General Population Genes Genetic Genetic Models Genomics Germ Cells Goals Health Imaging Techniques Infertility Knock-out Knockout Mice Laboratories Licensing Light Longevity Mammals Mediator Meiosis Menopause Microscopy Modeling Molecular Morphogenesis Mus Mutant Strains Mice Mutation National Institute of Child Health and Human Development Oocytes Oogenesis Optical Coherence Tomography Ovarian Ovary Paracrine Communication Pathologic Pathology Pathway interactions Perinatal mortality demographics Phenotype Play Population Primordial Follicle Proliferating Protein Dynamics Proteins Regulatory Pathway Reporter Reproduction Research Role Signal Pathway Signal Transduction Signaling Protein Smad Proteins Somatic Cell Specific qualifier value Sterility Strategic Planning Structure of primordial sex cell Subgroup Supporting Cell Testing Time Tissues Transforming Growth Factor beta Transplantation Woman antagonist cell type design egg exhaustion experimental study extracellular fetal genetic variant idiopathic infertility morphogens mutant novel oocyte quality ovarian reserve primary ovarian insufficiency protein function reproductive reproductive senescence reproductive system disorder response single cell sequencing subfertility transcriptome

项目摘要

PROJECT SUMMARY Normally, women undergo menopause in their early fifties due to exhaustion of the pool of oocytes called the “ovarian reserve”. Oocytes are generated in large numbers during embryonic development, but the vast majority undergo programmed cell death; the remaining oocytes become enclosed within quiescent primordial follicles that make up the ovarian reserve. Pathologic development of the ovarian reserve leads to infertility or early reproductive senescence. Furthermore, meiotic errors in oocytes cause germ cell death or result in developmental defects such as aneuploidy. The molecular signals within the embryonic ovary that determine the upper and lower limits for oocyte numbers are unknown. The long-term goal of our laboratory is to identify signaling pathways that control oogenesis and thus, female reproductive lifespan. The bone morphogenetic proteins (BMPs) are a large subgroup of the transforming growth factor beta family and have conserved roles in primordial germ cell specification and development. The BMPs are known morphogens whose activity must be strictly regulated during development or pathology and disease results. There are a number of secreted extracellular BMP-binding proteins that act as molecular sinks to negatively regulate the amount of BMP “sensed” by a signal-receiving cell. Two of these BMP antagonists, GREMLIN-1 and GREMLIN-2 have genetic variants associated with primary ovarian insufficiency (POI) in women. We tested the developmental role of Grem1 and Grem2 by generating single and double knockout mice for Grem1 and Grem2. These mice display a range of defects in embryonic ovary development including changes to oocyte number and altered meiosis. The aims of this proposal are designed to (1) determine how loss of Grem1 and/or Grem2 alters embryonic ovary development; and (2) determine which signaling pathways are dysregulated in embryonic ovaries of mutant mice that drive changes in germ cell numbers. Collectively, our studies stand to uncover fundamental mechanism that regulate embryonic ovary development and oocyte numbers, which are essential for mammalian female reproduction and reproductive lifespan.

项目概要通常，女性在五十岁出头时会因为卵母细胞耗尽而进入更年期。 “卵巢储备”在胚胎发育过程中大量产生，但数量巨大。大多数经历程序性细胞死亡；剩余的卵母细胞被封闭在静止的原始细胞中构成卵巢储备的卵泡卵巢储备的病理发育会导致不孕或不孕。此外，卵母细胞减数分裂错误会导致生殖细胞死亡或导致生殖细胞早期衰老。发育缺陷，例如非整倍体胚胎卵巢内决定的分子信号。卵母细胞数量的上限和下限未知，我们实验室的长期目标是确定。控制卵子发生从而控制女性生殖寿命的信号通路。蛋白质 (BMP) 是转化生长因子 β 家族的一个大亚组，在 BMP 是已知的形态发生素，其活性必须是原始生殖细胞的规范和发育。发育过程或病理学和疾病过程中受到严格调控的结果有许多。细胞外 BMP 结合蛋白充当分子汇，负向调节“感知”的 BMP 量其中两种 BMP 拮抗剂 GREMLIN-1 和 GREMLIN-2 具有遗传变异。与女性原发性卵巢功能不全 (POI) 相关我们测试了 Grem1 和的发育作用。 Grem2 通过生成 Grem1 和 Grem2 的单敲除和双敲除小鼠这些小鼠表现出一系列的特征。胚胎卵巢发育缺陷，包括卵母细胞数量的变化和减数分裂的改变。该提案旨在 (1) 确定 Grem1 和/或 Grem2 的缺失如何改变胚胎卵巢 (2) 确定突变小鼠胚胎卵巢中哪些信号通路失调总的来说，我们的研究揭示了推动生殖细胞数量变化的基本机制。调节胚胎卵巢发育和卵母细胞数量，这对雌性哺乳动物至关重要生殖和生殖寿命。