Epigenetic regulation of receptive endometrium

44岁以下的女性中有6%不孕，12%难以怀孕或足月妊娠，超过75%的失败妊娠涉及植入缺陷。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衰减与子宫内膜异位症不孕妇女有关。涉及狒狒和小鼠的诱导子宫内膜异位症动物模型显示，在子宫内膜异位症的进展过程中，HDAC3显著减少。子宫特异性Hdac3敲除小鼠由于着床和脱体细胞缺陷而不育。在本提案中，我们的中心假设是HDAC3维持对子宫内膜功能的类固醇激素调节，而HDAC3的缺失由于着床缺陷和脱胎化导致不孕。我们的目标是通过揭示HDAC3在子宫中的功能，以及表观遗传调控与卵巢类固醇激素信号传导的相关关系，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性不孕症的影响。该研究将促进不孕症和子宫内膜异位症的临床前药物治疗的发展，并为HDAC3和类固醇激素信号之间的分子联系提供证据，以加速对早期妊娠丢失的新兴治疗方法的评估。

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.