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揭开子宫内膜异位症降低女性生育力的根源和近端机制。有证据支持子宫内膜异位症与生育力下降之间的联系。可悲的是，因果关系尚未建立，因此，对于子宫内膜异位症患者的不孕症，缺乏有效的治疗方法。我们的总体假设是子宫内膜异位症导致生育力下降。我们假设的理由是基于临床观察和已发表的证据，支持子宫内膜异位症与生育力下降之间的联系。由于对生育力的研究在伦理上仅限于女性，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力。我们已报道子宫内膜异位症(Endo)大鼠新生的子宫内膜病变合成和分泌金属蛋白酶组织抑制因子-1(TIMP-1)，并且子宫内膜异位症(Endo)大鼠卵巢滤泡膜中的TIMP-1定位是Sham大鼠的两倍。已知TIMP-1高度调控卵泡发育、排卵和胚胎发育所需的基质金属蛋白酶(MMPs)，我们认为子宫内膜异位症TIMP-1可以阻断卵泡发育和排卵所需的卵巢MMPs。其他研究表明，在体内和体外，抑制MMPs的TIMP-1会导致胚胎生长迟缓和胚胎存活率下降。我们最新和最令人兴奋的初步数据显示，通过在培养液中添加TIMP-1或通过腹腔注射TIMP-1，Sham大鼠胚胎会出现子宫内膜异位症样异常。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是一致的，而且子宫内膜异位症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，并将在这个已建立的大鼠子宫内膜异位症模型中执行，并通过与来自人类卵巢、卵母细胞和胚胎的数据进行比较来验证。具体目的1：子宫内膜异位病变通过TIMP-1调节机制减少卵泡发育，阻碍排卵，从而降低生育力。特定目的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的生育力下降。确定子宫内膜异位症生育能力下降的特定表型是了解子宫内膜异位症发挥病理作用的机制的第一步，可能会开发新的、有针对性的恢复生育能力的方法。这种方法对于改变手术或化学治疗病变或反复尝试试管受精至关重要。使用模拟人类疾病的子宫内膜异位症模型，并将数据与来自女性的数据进行比较，将有助于进行机械性研究，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治疗子宫内膜异位症的新疗法的安全性和有效性，并将数据快速转化为对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与生育力下降之间的联系，但因果关系尚未建立，因此，对患有子宫内膜异位症的妇女的不孕不育缺乏有效的治疗方法。我们假设，子宫内膜异位症通过其合成和分泌TIMP-1的能力降低了生育力。众所周知，TIMP-1高度调控着卵泡发育、排卵和胚胎发育所需的MMPs，我们认为子宫内膜异位症TIMP-1阻断了正常功能所需的MMPs，降低了生育力。

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.