Epigenetic regulation of receptive endometrium

容受性子宫内膜的表观遗传调控

• 批准号: 10674101
• 负责人: Jae-Wook Jeong
• 金额: $ 43万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674101
• 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' 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

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% 不孕，12% 的女性难以怀孕或足月妊娠，超过 75% 的妊娠失败涉及着床缺陷。子宫内膜异位症困扰着超过10%的育龄妇女，是导致不孕的主要原因，但其病因尚不清楚。因此，确定子宫内膜异位症相关不孕症的发病机制至关重要。我们有证据表明 HDAC3 减弱与患有子宫内膜异位症的不孕女性有关。狒狒和小鼠的诱发子宫内膜异位症动物模型显示，在子宫内膜异位症进展过程中，HDAC3 显着减少。子宫特异性 Hdac3 敲除小鼠由于着床和蜕膜化缺陷而无法生育。在该提案中，我们的中心假设是HDAC3维持类固醇激素对子宫内膜功能的调节，并且HDAC3的缺失会因着床和蜕膜化缺陷而导致不孕。我们的目标是通过揭示 HDAC3 在子宫中的功能以及表观遗传调控和卵巢类固醇激素信号传导的相关性来帮助解决不孕症和子宫内膜疾病。首先，我们将确定 HDAC3 的病理生理作用。其次，我们将确定 HDAC3 缺失对子宫内膜异位症相关不孕症的影响。拟议的研究将推动针对不孕症和子宫内膜异位症的临床前药物疗法的开发，并提供 HDAC3 和类固醇激素信号传导之间分子联系的证据，以加速对针对早期妊娠流产的新兴疗法的评估。