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

子宫内膜异位症生育力降低的机制：MMP 和 TIMP 的作用

• 批准号: 7524056
• 负责人: KATHY L TIMMS
• 金额: $ 31.77万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524056
• 关键词: Adoptive Transfer; Animal Model; Biological Markers; Blocking Antibodies; Chemicals; Clinical; Compatible; Culture Media; Data; Development; Embryo; Embryonic Development; Environment; Enzymes; Female; Fertility; Fertility Study; Fertilization; Fertilization in Vitro; Genes; Goals; Growth; Harvest; Human; In Vitro; Infertility; Inhibition of Matrix Metalloproteinases Pathway; Injection of therapeutic agent; Intra-abdominal; Knowledge; Lead; Lesion; Localized; Matrix Metalloproteinases; Metaphase; Modeling; Morphology; Numbers; Oocytes; Operative Surgical Procedures; Ovarian; Ovary; Ovulation; Pattern; Peritoneal Fluid; Personal Satisfaction; Phenotype; Placebos; Plant Roots; Pre-implantation Embryo Development; Pregnancy Rate; Proteins; Public Health; Publishing; Rattus; Records; Reporting; Research; Role; Safety; Specificity; Testing; Tissue Inhibitor of Metalloproteinase-1; Translations; Woman; base; blastocyst; data modeling; design; embryo cell; endometriosis; human data; human disease; in vivo; novel; novel therapeutics; restoration; zygote

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.

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。有证据支持子宫内膜异位症与生育力降低之间的关联。不幸的是，因果关系尚未建立，因此严重缺乏针对子宫内膜异位症女性不孕症的有效治疗方法。我们的总体假设是子宫内膜异位症会导致生育力下降。我们的假设的基本原理是基于临床观察和已发表的支持子宫内膜异位症与生育力降低之间关联的证据。由于对女性生育力的研究在伦理上受到限制，我们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力。我们报道，子宫内膜异位症病变从头合成并分泌金属蛋白酶-1（TIMP-1）组织抑制剂，并且子宫内膜异位症（Endo）大鼠的卵巢卵泡膜中的子宫内膜异位症TIMP-1比假手术大鼠多两倍。众所周知，TIMP-1 高度调节对卵泡发育、排卵和胚胎发育至关重要的基质金属蛋白酶 (MMP)，因此我们认为子宫内膜异位的 TIMP-1 会阻断卵泡发育和排卵所需的卵巢 MMP。其他人已经表明，TIMP-1 对 MMP 的抑制，无论是在体内还是在体外，都会导致胚胎生长迟缓和胚胎存活率降低。我们最新且最令人兴奋的初步数据显示，通过在培养基中添加 TIMP-1 或通过腹内注射 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以及子宫内膜异位症 TIMP-1 可能是导致这些异常的机制的一部分的观点是一致的。已经设计了两个假设驱动的具体目标，并将在大鼠子宫内膜异位症模型中进行实施，并通过与人类卵巢、卵母细胞和胚胎的数据比较进行验证。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 2：子宫内膜异位症病变 TIMP-1 会导致卵母细胞质量和胚胎发育的特定异常，从而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具体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。这些方法对于改变手术或化学消融病变或反复尝试体外受精的做法至关重要。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，并提供测试子宫内膜异位症新治疗方法的安全性和有效性的途径，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：有证据支持子宫内膜异位症与生育力下降之间存在关联，但因果关系尚未确定，因此严重缺乏针对子宫内膜异位症女性不孕症的有效治疗方法。我们假设子宫内膜异位症通过其合成和分泌 TIMP-1 的能力来降低生育力。众所周知，TIMP-1 高度调节对卵泡发育、排卵和胚胎发育至关重要的 MMP，我们认为子宫内膜异位的 TIMP-1 会阻断正常功能所需的 MMP，并降低生育力。