Epigenetic regulation of receptive endometrium

44岁以下的女性中有6%不孕，12%难以怀孕或怀孕到足月，超过75%的失败怀孕涉及植入缺陷。子宫内膜异位症，困扰着超过10%的育龄妇女，是不孕症的主要原因，但其病因尚不清楚。因此，确定糖尿病相关不孕症发病机制至关重要。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的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基因敲除小鼠由于着床和蜕膜化缺陷而不育。在这个提议中，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，HDAC3缺失导致由于植入和蜕膜化缺陷而导致的不孕。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节和卵巢类固醇激素信号传导如何相关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缺失对糖尿病相关不孕症的影响。这项拟议的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，并提供HDAC 3和类固醇激素信号传导之间分子联系的证据，以加速对早期妊娠丢失的新兴疗法的评估。

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.