Mechanisms of Reduced Fecundity in Endometriosis: A role for MMPs and TIMPs

6.项目总结 我们研究的长期目标是揭开子宫内膜异位症的根源和近端机制 会降低女性的生育力。证据支持子宫内膜异位症与减少之间的联系 繁殖力。可悲的是，因果关系尚未建立，因此有效的治疗 子宫内膜异位症患者的不孕症严重缺乏。我们的总体假设是子宫内膜异位症 会导致生育力下降。我们假设的基本原理是基于临床观察并发表的。 支持子宫内膜异位症与生育力下降之间联系的证据。因为对生育力的研究 在伦理上仅限于女性，我们已经使用已建立的子宫内膜异位症动物模型来开始了解 子宫内膜异位症如何降低生育能力。我们已经报道了子宫内膜异位症病变的新生合成和 分泌金属蛋白酶组织抑制因子-1(TIMP-1)，子宫内膜异位症TIMP-1定位增加一倍 子宫内膜异位症(Endo)大鼠与假手术大鼠的卵巢卵泡膜。众所周知，TIMP-1 高度调控基质金属蛋白酶(MMPs)，对卵泡发育、排卵和 胚胎发育，我们认为子宫内膜异位症TIMP-1正在阻断卵泡所需的卵巢MMPs 发育和排卵。其他研究表明，TIMP-1在体内和体外都能抑制MMPs， 会导致胚胎发育迟缓和胚胎存活率下降。我们最新最令人兴奋的 初步数据显示，假大鼠胚胎通过向胚胎中添加TIMP-1来发展子宫内膜异位症样异常 培养上清液或腹腔注射TIMP-1。总的来说，这些数据与概念是一致的 子宫内膜异位症导致卵巢、卵母细胞和胚胎异常以及子宫内膜异位症TIMP-1可能是 造成它们的机制。已经设计了两个假设驱动的具体目标，并将 用这种已建立的大鼠子宫内膜异位症模型进行实验，并通过与 人类卵巢、卵母细胞和胚胎。具体目标1：子宫内膜异位病变减少卵泡发育 并通过TIMP-1调节机制阻碍排卵，从而减少繁殖力。具体目标2： 子宫内膜异位症病变TIMP-1导致卵母细胞质量和胚胎发育的特殊异常 导致子宫内膜异位症患者生育力下降。低繁殖力的特定表型的测定 子宫内膜异位症是了解子宫内膜异位症的作用机制的第一步。 病理效应、新的、有针对性的恢复生育能力的方法可能会被开发出来。这样的方法 最重要的是从手术或化学清除病变或反复尝试试管受精转变。使用 模拟人类疾病的子宫内膜异位症模型，并将数据与女性的数据进行比较，将有助于 机制研究，以确定子宫内膜异位症如何降低生育力，并提供了一种途径，以测试 子宫内膜异位症新治疗方法的安全性和有效性，以及将数据快速转化为 人类子宫内膜异位症的知识。NARRITAVE计划 有证据支持子宫内膜异位症与生育力下降之间存在因果关系 这种关系尚未建立，因此有效的治疗子宫内膜异位症不孕症的方法是 可悲的是缺乏。我们假设，子宫内膜异位症通过其合成和分泌能力来降低生育力。 TIMP-1。众所周知，TIMP-1高度调控MMPs，MMPs对卵泡发育、排卵和 胚胎发育，我们认为子宫内膜异位症TIMP-1正在阻断正常功能所需的MMPs和 减少繁殖力。

6. PROJECT SUMMARY The long term goal of our research is to unravel root and proximal mechanisms by which endometriosis decreases fecundity in women. Evidence supports an association between endometriosis and reduced fecundity. Tragically, a cause and effect relationship has not been established, hence effective treatments for infertility in women with endometriosis are woefully lacking. Our overall hypothesis is that endometriosis causes reduced fecundity. The rationale for our hypothesis is based on clinical observations and published evidence supporting an association between endometriosis and reduced fecundity. As studies of fertility are ethically limited in women, we have used an established endometriosis animal model to begin to understand how endometriosis reduces fecundity. We have reported that endometriotic lesions de novo synthesize and secrete tissue inhibitor of metalloproteinase-1 (TIMP-1) and that two-fold more endometriotic TIMP-1 localizes in the ovarian follicular theca in endometriosis (Endo) rats compared to Sham rats. As it is known that TIMP-1 highly regulates matrix metalloproteinase enzymes (MMPs) critical for follicular development, ovulation and embryo development, we propose endometriotic TIMP-1 is blocking ovarian MMPs required for follicular development and ovulation. Others have shown that TIMP-1 inhibition of MMPs, both in vivo and in vitro, causes embryo growth retardation and reduction in embryo survival. Our newest and most exciting preliminary data shows Sham rat embryos develop endometriosis-like anomalies by addition of TIMP-1 to culture media or by intra-abdominal injection of TIMP-1. Collectively, these data are compatible with the notion that endometriosis causes ovarian, oocyte and embryo anomalies and that endometriotic TIMP-1 may be part of the mechanism causing them. Two hypothesis-driven Specific Aims have been designed and will be performed with this established model of endometriosis in the rat and validated by comparison to data from human ovaries, oocytes and embryos. Specific Aim 1: Endometriotic lesions diminish follicular development and impede ovulation via a TIMP-1 modulated mechanism thereby reducing fecundity. Specific Aim 2: Endometriotic lesion TIMP-1 causes specific anomalies in oocyte quality and embryo development contributing to reduced fecundity in endometriosis. Determining the specific phenotype of reduced fecundity in endometriosis is the first step towards understanding mechanisms whereby endometriosis exerts its pathological effects, novel, targeted approaches for restoration of fertility may be developed. Such approaches are paramount to shift from surgical or chemical obliteration of lesions or repeated attempts at IVF. Using an endometriosis model which emulates human disease and comparing the data to that from women will facilitate mechanistic studies to determine how endometriosis reduces fecundity and provide an avenue to test the safety and efficacy of novel therapeutic approaches for endometriosis, and a rapid translation of data into knowledge of human endometriosis. 7. PROJECT NARRITAVE Evidence supports an association between endometriosis and reduced fecundity yet a cause and effect relationship has not been established, hence effective treatments for infertility in women with endometriosis are woefully lacking. We hypothesize that endometriosis reduces fecundity via its ability to synthesize and secrete TIMP-1. As it is known that TIMP-1 highly regulates MMPs critical for follicular development, ovulation and embryo development, we propose endometriotic TIMP-1 is blocking MMPs required for normal function and reducing fecundity.