FUNCTION OF HB/EGF IN UTERINE STROMAL CELLS

子宫功能障碍和疾病通常是由于 调节细胞增殖。举个例子，子宫内膜癌， 子宫内膜异位症、子宫肌瘤均以异常细胞为特征 扩散。此外，子宫内膜不足或不同步 增殖和发育是不孕不育的常见原因。如果 子宫细胞调控中的细胞或组织特异性步骤 增殖是已知的，子宫特异的调节分子，可以 作为靶向治疗的基础，以控制扩散和 子宫疾病的辨证论治。其结果是， 目前的治疗方法可以避免这种结果。需要黄体酮 支持细胞的增殖和分化(蜕膜化) 子宫基质细胞，但对其分子知之甚少 黄体酮刺激的导致有丝分裂或 蜕膜化。我们已经证明了肝素结合的表皮 孕酮刺激HB-EGF表达的实验研究 子宫基质细胞和抑制HB-EGF功能也抑制 蜕膜化。因此，孕酮和HB-EGF是唯一 已被证明是 蜕膜化。拟议的研究项目旨在阐明 HB-EGF调节分子通路的机制 导致子宫基质细胞增殖，并确定如何 增殖控制蜕膜化。我们的项目将测试 蜕膜化依赖孕酮诱导的假说 HB-EGF介导的间质细胞增殖。特定目标 1将测试假设的增殖途径，以确定HB-EGF如何 调节基质细胞的增殖，HB-EGF本身是如何调节的 这一途径，以及哪些其他蛋白质对基质细胞是必不可少的 扩散。具体目标2将确定扩散的步骤 阻断特异性蜕膜化所必需的途径 子宫基质细胞周期的不同阶段。《特定目标3》将测试一个 建立体内增殖途径模型并鉴定额外的蛋白质 治疗干预的靶点。的结果模型 子宫基质细胞增殖及调控的分子途径 去中心化将为发展……提供基本基础。 选择性、有针对性地治疗源于 不受控制的细胞增殖。

Uterine dysfunction and disease often result from the disruption of regulated cell proliferation. As examples, endometrial carcinoma, endometrosis, and leiomyoma are all characterized by abnormal cell proliferation. In addition, insufficient or asynchronous endometrial proliferation and development is a frequent cause of infertility. If cell or tissue-specific steps in the regulation of uterine cell proliferation were known, uterine-specific regulatory molecules, could serve as the basis of targeted therapies to control proliferation and differentiation in uterine disease. As a result, side-effects which result from current therapies could be avoided. Progesterone is required to support both proliferation and differentiation (decidualization) of uterine stromal cells, but very little is known of the molecular pathways stimulated by progesterone which lead to mitosis or decidualization. We have demonstrated that heparin-binding epidermal growth factor (HB-EGF) expression is stimulated by progesterone in uterine stromal cells and that inhibiting HB-EGF function also inhibits decidualization. Therefore, progesterone and HB-EGF are the only molecules which have been demonstrated to be essential for decidualization. The proposed research project is designed to elucidate the mechanisms through which HB-EGf regulates the molecular pathway leading to uterine stromal cell proliferation, and determine how proliferation controls decidualization. Our project will test the hypothesis that decidualization is dependent on progestrone-induced stroma cell proliferation, which is mediated by HB-EGF. Specific Aim 1 will test a hypothetical proliferation pathway to determine how HB-EGF regulates stromal cell proliferation, how HB-EGF itself is regulated in this pathway, and what other proteins are essential for stromal cell proliferation. Specific Aim 2 will define steps in the proliferation pathway which are essential for decidualization by blocking specific phases of the uterine stromal cell cycle. Specific Aim 3 will test a model proliferation pathway in vivo and identify additional protein targets for therapeutic intervention. The resulting model of the molecular pathway for uterine stromal cell proliferation and decidualization will provide a basic foundation for the development of selective, targeted, therapies for uterine diseases derived from unregulated cell proliferation.