INTERLEUKIN-1 IN HUMAN IMPLANTATION

植入生物学是最重要但却知之甚少的学科之一。 女性健康问题。人类胚胎未能植入或有缺陷 植入导致随后的妊娠丢失是一种主要的临床表现。 人类生殖生物学中的问题。美国9对情侣之一 各州不由自主地没有孩子，据估计，只有三分之一的人 潜在的生育周期导致孩子大约有30%的 胚胎永远不会到达子宫植入阶段，再有30% 这些植入物在形态上是不正常的和不能存活的。更多 最近，对人绒毛膜促性腺激素(HCG)进行了敏感的检测 在hCG检测发现的所有妊娠中，有22%未能检测到 存活的时间足够长，可以得到临床上的认可。因此，该病的发病率 临床上未识别的植入失败率很高。此外, 临床诊断为妊娠的自然流产率为15%-25%。 近年来，妊娠损耗和习惯性的几种免疫学病因 虽然有人提议堕胎，但人们对堕胎的可能性知之甚少。 妊娠损耗的免疫学发病机制。在这项提案中，我们将 探讨IL-1系统--其受体IL-1β 拮抗剂--在人体植入过程中起着关键作用。我们的第一次 目的：研究IL-1受体I型(IL-1Rti)在人体内的调节作用 子宫内膜间质和腺体细胞培养。这些研究将 检测IL-1β及其他细胞因子和生长因子的能力 调节和上调子宫内膜IL-IR蛋白和RNA的表达。 此外，细胞分泌的生长因子和细胞因子的能力 人类胚胎对子宫内膜IL-IR水平的调节将使用 人类胚胎条件培养液。第二个目标将检查能力 IL-1β作为调节纤溶酶原激活系统的重要因子 子宫内膜反应允许胚胎侵袭的机制及机制 植入。这项研究的第三个目标是检查子宫内膜 白介素1受体拮抗剂(IL-1)的定位和体外调节 人子宫内膜腺和间质细胞中1ra)基因和蛋白的表达 培养和IL-1ra抑制IL-1上调的能力 受体受IL-Ibeta和其他生长因子的影响。第四个目标是学习 IL-1ra对人胚泡着床的体内效应 注射PMSG/hCG对着床和妊娠的影响 刺激交配的小鼠。 我们的假设是IL-1的适当激活和上调 由IL-1β和其他胚胎产生的细胞因子产生的受体 对成功植入人类胚胎至关重要。推论是IL- 1ra能够干扰植入成功。澄清： 细胞因子介导的胚胎与子宫内膜的关系 在早期着床过程中对理解 与植入相关的临床重要不孕症 失败和习惯性流产；这样的知识将拓宽我们的 对植入早期事件的了解，并有潜力 妊娠消瘦证候的临床应用。

Implantation biology is one of the most important yet least understood women's health issues. Failure of the human embryo to implant or faulty implantation resulting in subsequent pregnancy loss is a major clinical problem in human reproductive biology. One of 9 couples in the United States is involuntarily childless and it is estimated that only 1/3 of potentially fertile cycles result in a child with approximately 30% of embryos never reaching the stage of uterine implantation ad another 30% which implant but are morphologically abnormal and non-viable. More recently, sensitive assays for human chorionic gonadotropin (hCG) have documented that 22% of all pregnancies detected by hCG assay fail to survive long enough to be clinically recognized. Thus, the incidence of clinically unrecognized implantation failure is high. In addition, spontaneous abortion rates are 15-25% for clinically diagnosed pregnancies. Recently, several immunologic etiologies for pregnancy wastage and habitual abortion have been proposed but little is actually known about the possible immunologic pathogenesis of pregnancy wastage. In this proposal, we will investigate the hypothesis that the IL-1 system --IL - 1beta, its receptor antagonist -- are critical in the process of human implantation. Our first goal is to study the regulation of IL-1 receptor type I (IL-1R tI) in human endometrial stromal and glandular cell cultures. These studies will examine the ability of IL-1beta and other cytokines and growth factors to modulate and upregulate protein and RNA expression of endometrial IL-IR tI. In addition, the ability of growth factors and cytokines secreted by the human embryo to modulate endometrial IL-IR tI levels will be assessed using human embryo-conditioned media. The second goal will examine the ability of IL-1beta to modulate the plasminogen activator system as an important mechanism of endometrial response permitting embryonic invasion and implantation. The third goal of this study is to examine the endometrial localization and in vitro regulation of both IL-1 receptor antagonist (IL- 1ra) mRNA and protein in human endometrial glandular and stromal cell cultures and the ability of IL-1ra to ablate upregulation of the IL-1 receptor by IL-Ibeta and other growth factors. The fourth goal is to study the in vivo effect of Il-1ra on implantation by examining its ability to interfere with implantation and pregnancy when injected into PMSG/hCG stimulated and mated mice. Our hypothesis is that appropriate activation and upregulation of the IL-1 receptor by IL-1beta and by other embryonically generated cytokines is critical to successful human embryo implantation. A corollary is that IL- 1ra is capable of interfering with successful implantation. Elucidation of the cytokine mediated relationship between the embryo and endometrium during early implantation is critical to the understanding of the clinically important entities of infertility related to implantation failure and habitual abortion; such knowledge will broaden our understanding of the events of early implantation and has potential clinical application in syndromes of pregnancy wastage.