Developmental effects of endometriosis on fertility of future generations

 描述(由申请人提供)：我们的长期目标是揭开子宫内膜异位症导致女性家庭不孕的机制。子宫内膜异位症生育力下降的原因仍然是生殖医学中最大的谜团之一。有证据支持子宫内膜异位症和跨代不孕症之间的联系，但因果关系尚不清楚。这导致每年在医疗保健上花费数十亿美元 用于症状驱动的非治愈性治疗方法。该项目将测试子宫内膜异位症在子宫内暴露会导致后代多代生殖异常的探索性假设，以及在三代人中配子和植入前胚胎中基因表达的重新编程，这将转化为新的、不可预见的治疗方法，以恢复患有子宫内膜异位症妇女的生育能力。具体目的1：胚胎子宫内膜异位症或胚胎生殖细胞的发育性(宫内)暴露在Endo与对照组大鼠三代子代中表现为产仔和后代特征异常、配子质量差和胚胎发育延迟/停滞。特定目的2：子宫内膜异位症的不育症是由于配子DNA甲基化和/或组蛋白修饰(卵母细胞/精子印迹)的分子异常以及胚胎中的表观遗传DNA修饰和染色质重组以性别特异性的方式引起的，从而改变了三代Endo大鼠配子功能和胚胎发育的关键基因表达途径。破译子宫内膜异位症影响多代人生育的分子机制，将有助于发现主要靶点，以开发革命性的临床干预措施，解决子宫内膜异位症妇女不孕不育的原因甚至预防。这些研究将首次确定多代传播是否会通过女性和/或男性导致胚胎基因表达的变化。这对人类生殖健康的意义是巨大的。这些新的干预措施对于从手术或化学治疗病变或多次试管受精失败的尝试中演变出来是至关重要的。它们还提供了一种途径来测试新的改变范式的临床干预措施的安全性和有效性，并帮助将知识从试验台快速转化到不孕不育诊所。

 DESCRIPTION (provided by applicant): Our long-term objective is to unravel mechanisms by which endometriosis causes infertility in females within families. The cause of reduced fecundity in endometriosis remains one of the greatest enigmas in reproductive medicine. Evidence supports an association between endometriosis and transgenerational infertility, yet the cause and effect relationship is unknown. This leads to billions of dollars spent annually on health care for symptom-driven, non-curative therapeutic approaches. This project will test the exploratory hypothesis that in utero exposure to endometriosis causes multigenerational reproductive anomalies in the offspring and reprogramming of gene expression in gametes and preimplantation embryos in three generations, which will translate into novel, unforeseen treatments to restore fertility in women with endometriosis. Specific Aim 1: Developmental (in utero) exposure to endometriosis of embryos or the embryo's embryonic germ cells manifests as abnormal litter and offspring characteristics, poor gamete quality and delayed/arrested embryo development in three generations of progeny from Endo vs. Control rats. Specific Aim 2: Subfertility in endometriosis is caused by molecular aberrations in DNA methylation and/or histone modifications of gametes (oocyte/sperm imprinting) and epigenetic DNA modifications and chromatin reorganization in embryos in a sex-specific manner thus altering gene expression pathways critical for gamete function and embryo development in three generations of Endo rats. Deciphering molecular mechanisms by which endometriosis disrupts fertility across multiple generations will facilitate discovery of prime targets for development of revolutionizing clinical interventions addressing the cause or even prevention of subfertility in women with endometriosis. These studies will be the first to determine whether multigenerational transmission causes alterations in embryo gene expression via the female and/or male. The significance to human reproductive health is enormous. These new interventions are paramount to evolve from surgical or chemical obliteration of lesions or repeated unsuccessful attempts at IVF. They also provide an avenue to test safety and efficacy of new paradigm changing clinical interventions and assist rapid translation of knowledge from the bench to the infertility clinic.