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

描述（由申请人提供）：我们研究的长期目标是解开子宫内膜异位症降低女性生育力的根源和近端机制。证据支持子宫内膜异位症和生育力降低之间的关联。可悲的是，因果关系尚未建立，因此子宫内膜异位症妇女不孕症的有效治疗方法非常缺乏。我们的总体假设是子宫内膜异位症导致生育力下降。我们的假设是基于临床观察和已发表的证据，支持子宫内膜异位症和生育力下降之间的关联。由于生育力的研究在伦理学上局限于女性，我们使用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力。我们已经报道，异位病灶从头合成和分泌金属蛋白酶组织抑制剂-1（TIMP-1），并且与假手术大鼠相比，异位TIMP-1定位于子宫内膜异位症（Endo）大鼠的卵巢卵泡膜中。由于TIMP-1对卵泡发育、排卵和胚胎发育至关重要的基质金属蛋白酶（MMP）具有高度调节作用，因此我们提出，卵巢癌TIMP-1阻断卵泡发育和排卵所需的卵巢MMP。其他人已经表明，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。我们最新的和最令人兴奋的初步数据显示，假手术大鼠胚胎发展类胚胎发育异常的TIMP-1的培养基或腹腔注射TIMP-1。总的来说，这些数据与子宫内膜异位症导致卵巢、卵母细胞和胚胎异常的观点一致，子宫内膜异位症TIMP-1可能是导致这些异常的机制的一部分。已经设计了两个假设驱动的特定目标，并将在大鼠中使用该已建立的子宫内膜异位症模型进行，并通过与来自人卵巢、卵母细胞和胚胎的数据进行比较来验证。具体目标1：子宫内膜异位病变通过TIMP-1调节机制减少卵泡发育并阻碍排卵，从而降低生育力。具体目标二：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异性异常，导致子宫内膜异位症的生育力降低。确定子宫内膜异位症中生育力降低的特定表型是了解子宫内膜异位症发挥其病理作用的机制的第一步，可以开发新的，有针对性的恢复生育力的方法。这些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，并提供一种途径来测试子宫内膜异位症新治疗方法的安全性和有效性，并将数据快速转化为人类子宫内膜异位症的知识。公共卫生相关性：证据支持子宫内膜异位症和生育力下降之间的关联，但因果关系尚未建立，因此子宫内膜异位症女性不孕症的有效治疗方法非常缺乏。我们推测子宫内膜异位症通过其合成和分泌TIMP-1的能力降低生育力。由于已知TIMP-1高度调节对卵泡发育、排卵和胚胎发育至关重要的MMPs，因此我们提出异位TIMP-1阻断正常功能所需的MMPs并降低生育力。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.