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

6.项目摘要 我们研究的长期目标是解开子宫内膜异位症的根源和近端机制， 降低女性的生育能力。有证据支持子宫内膜异位症与子宫内膜异位症的发病率降低之间存在关联。 繁殖力不幸的是，因果关系尚未建立，因此有效的治疗方法 子宫内膜异位症妇女不孕症的严重缺乏。我们的假设是子宫内膜异位症 导致繁殖力下降。我们假设的基本原理是基于临床观察和发表的 支持子宫内膜异位症和生育力降低之间存在关联的证据。正如生育率的研究 由于伦理学上的局限性，我们使用了一个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，新生的肿瘤病变合成， 分泌金属蛋白酶组织抑制剂-1（TIMP-1），且两倍多的促炎性TIMP-1定位于 与假手术大鼠相比，子宫内膜异位症（Endo）大鼠的卵巢卵泡膜中。众所周知，TIMP-1 高度调节基质金属蛋白酶（MMPs），对卵泡发育、排卵和 在胚胎发育中，我们提出卵巢癌TIMP-1阻断卵泡发育所需的卵巢MMPs， 发育和排卵。其他研究表明，体内和体外MMP的TIMP-1抑制， 导致胚胎生长迟缓和胚胎存活率降低。我们最新和最令人兴奋的 初步数据显示，假鼠胚胎通过加入TIMP-1， 培养基或通过腹腔内注射TIMP-1。总的来说，这些数据符合这样一个概念， 子宫内膜异位症导致卵巢、卵母细胞和胚胎异常，异位性TIMP-1可能是子宫内膜异位症的一部分， 产生它们的机制。两个假设驱动的具体目标已经设计，并将 用这种建立的大鼠子宫内膜异位症模型进行，并通过与来自 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，从而降低生育力。具体目标二： 子宫内膜异位病变TIMP-1导致卵母细胞质量和胚胎发育的特异性异常， 降低子宫内膜异位症的生育力确定生殖力下降的特定表型 子宫内膜异位症是了解子宫内膜异位症发挥其 病理学效应，可以开发用于恢复生育力的新的靶向方法。这样的方法 对于从手术或化学闭塞病变或反复尝试IVF的转变至关重要。使用 子宫内膜异位症模型，模拟人类疾病，并比较数据，从妇女将有助于 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，以及数据的快速转化， 人类子宫内膜异位症的知识7.项目叙述 证据支持子宫内膜异位症和生育力下降之间的联系，但因果关系 相关性尚未建立，因此子宫内膜异位症女性不孕症的有效治疗方法是 可悲的缺乏。我们推测子宫内膜异位症通过其合成和分泌能力降低生育力 TIMP-1。众所周知，TIMP-1高度调节对卵泡发育、排卵和排卵至关重要的MMP。 在胚胎发育过程中，我们提出，抗肿瘤的TIMP-1阻断了正常功能所需的MMP， 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.