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示子宫内膜异位症降低女性生育能力的根本和近端机制。证据支持子宫内膜异位症与生育能力下降之间的联系。不幸的是，因果关系尚未建立，因此，对子宫内膜异位症妇女不孕的有效治疗非常缺乏。我们的总体假设是子宫内膜异位症导致生育能力下降。我们假设的基本原理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能力下降之间的联系。由于对女性生育能力的研究在伦理上受到限制，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是如何降低生育能力的。我们已经报道，子宫内膜异位症（Endo）大鼠的子宫内膜异位症病变重新合成并分泌组织抑制剂金属蛋白酶-1 (TIMP-1)，并且与Sham大鼠相比，子宫内膜异位症（Endo）大鼠的卵巢滤泡膜中的TIMP-1是Sham大鼠的两倍。由于已知TIMP-1高度调节基质金属蛋白酶（MMPs）对卵泡发育、排卵和胚胎发育至关重要，我们提出子宫内膜异位症TIMP-1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，TIMP-1对MMPs的抑制会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，通过向培养基中添加TIMP-1或腹腔内注射TIMP-1，假大鼠胚胎会发生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，子宫内膜异位症的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异性目标，并将在大鼠子宫内膜异位症的建立模型中进行，并通过与人类卵巢、卵母细胞和胚胎的数据进行比较来验证。特异性目的1：子宫内膜异位症病变通过TIMP-1调节机制减少卵泡发育并阻碍排卵，从而降低生育能力。特异性目的2：子宫内膜异位症病变TIMP-1引起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能力降低。确定子宫内膜异位症中生育能力降低的具体表型是了解子宫内膜异位症发挥其病理作用机制的第一步，可能会开发出新的、有针对性的恢复生育能力的方法。这些方法对于从手术或化学清除病变或反复尝试试管婴儿是至关重要的。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能力，并为测试子宫内膜异位症新治疗方法的安全性和有效性提供途径，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与生育能力下降之间存在关联，但尚未建立因果关系，因此严重缺乏对子宫内膜异位症妇女不孕症的有效治疗。我们假设子宫内膜异位症通过其合成和分泌TIMP-1的能力来降低生育能力。众所周知，TIMP-1高度调控对卵泡发育、排卵和胚胎发育至关重要的MMPs，我们认为子宫内膜异位症的TIMP-1阻断了正常功能所需的MMPs，降低了生育能力。

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.