Epigenetic regulation of receptive endometrium

容受性子宫内膜的表观遗传调控

基本信息

批准号：
10231662
负责人：
Jae-Wook Jeong
金额：
$ 60.68万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10231662
关键词：
Age Animal Model Assisted Reproductive Technology Biological Factors Biological Models COVID-19 pandemic Data Decidual Cell Reactions Defect Development Disease Endometrial Endometrial Stromal Cell Endometrium Epigenetic Process Etiology Evaluation Female Female infertility Fertility Fluorescence Gene Expression Regulation Genes HDAC3 gene Histone Acetylation Histone Deacetylase Homeostasis Human Infertility Knockout Mice Lead Lesion Link Luciferases Modeling Molecular Mus National Institute of Child Health and Human Development Ovarian Steroid Hormone Papio Pathogenesis Pharmacotherapy Preclinical Drug Development Pregnancy Prevalence Procedures Reporter Genes Resistance Role Sampling Signal Transduction Sterility Strategic Planning Testing Time Translational Research Ultrasonography Uterus Woman Women&apos s Health attenuation bioluminescence imaging cost early pregnancy early pregnancy loss endometriosis endometriosis-related infertility epigenetic regulation epigenomics eutopic endometrium experimental study hormonal signals hormone regulation human subject implantation in vivo in vivo imaging innovation mouse model pregnancy failure pregnant reproductive reproductive tract restoration steroid hormone transcriptomics translational study uterine receptivity

项目摘要

Six percent of women under 44 are infertile, 12% have difficulty getting pregnant or carrying pregnancies to term, and over 75% of failed pregnancies involve implantation defects. Endometriosis, afflicting more than 10% of women of reproductive age, is a major cause of infertility, but its etiology is unclear. Therefore, identification of mechanisms involved in the pathogenesis of endometriosis-related infertility are critical. We have evidence that HDAC3 attenuation is implicated in infertile women with endometriosis. Induced endometriosis animal models involving baboons and mice showed a significant reduction of HDAC3 during the progression of endometriosis. Uterine-specific Hdac3 knock-out mice were sterile due to a defect of implantation and decidualization. In this proposal, our central hypothesis is that HDAC3 maintains steroid hormone regulation for endometrial functions, and HDAC3 loss causes infertility due to defects of implantation and decidualization. Our objective is to help solve infertility and endometrial diseases by revealing how HDAC3 functions in the uterus, and how epigenetic regulation and ovarian steroid hormone signaling are correlated. First, we will determine the pathophysiological role of HDAC3. Second, we will determine the effects of HDAC3 loss on endometriosis-related infertility. The proposed study will motivate the development of preclinical drug therapies for infertility and endometriosis and provide evidence of the molecular link between HDAC3 and steroid hormone signaling in order to accelerate evaluation of an emerging therapy against early pregnancy loss.

44岁以下的女性中有6％的女性是不育，12％的妇女难以怀孕或怀孕，而怀孕的75％以上涉及植入缺陷。子宫内膜异位症遭受了超过10％的生殖年龄妇女，是不育的主要原因，但其病因尚不清楚。因此，鉴定与子宫内膜异位相关的不育症的发病机理涉及的机制至关重要。我们有证据表明HDAC3衰减与子宫内膜异位症的不育女性有关。涉及狒狒和小鼠的子宫内膜异位症模型在子宫内膜异位症进展过程中显示出HDAC3的显着降低。子宫特异性的HDAC3基因敲除小鼠由于植入和斜视性缺陷而无菌。在该提案中，我们的中心假设是HDAC3维持子宫内膜功能的类固醇激素调节，HDAC3损失导致由于植入和cant植的缺陷而导致不育症。我们的目标是通过揭示子宫中HDAC3的功能以及表观遗传调节和卵巢类固醇激素信号的相关性来帮助解决不育和子宫内膜疾病。首先，我们将确定HDAC3的病理生理作用。其次，我们将确定HDAC3损失对子宫内膜异位相关的不育症的影响。拟议的研究将激发临床前药物疗法的不育症和子宫内膜异位症的发展，并提供了HDAC3与类固醇激素信号传导之间的分子联系的证据，以便加快对早期妊娠丧失的新兴治疗的评估。