FUNCTION OF HB/EGF IN UTERINE STROMAL CELLS

子宫功能障碍和疾病往往是由于中断的 调节细胞增殖。 例如，子宫内膜癌， 子宫内膜异位症、子宫内膜异位症和子宫肌瘤都以异常细胞为特征 增殖 此外，子宫内膜不全或不同步 增殖和发育是不孕症的常见原因。 如果 子宫细胞调节中的细胞或组织特异性步骤 增殖是已知的，子宫特异性调节分子，可以 作为控制增殖的靶向治疗的基础， 子宫疾病的分化。 因此，副作用， 目前的治疗方法可以避免。需要Progressive 支持细胞增殖和分化（蜕膜化）， 子宫基质细胞，但很少有人知道的分子 由孕酮刺激的导致有丝分裂的途径， 蜕膜化 我们已经证明，肝素结合表皮 生长因子（HB-EGF）的表达受到孕酮的刺激， 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 这些分子已经被证明是 蜕膜化 拟议的研究项目旨在阐明 HB-EGF调节分子途径的机制 导致子宫间质细胞增殖，并确定如何 增殖控制蜕膜化。 我们的项目将测试 蜕膜化依赖于孕激素诱导 基质细胞增殖，这是由HB-EGF介导的。 具体目标 1将测试假设的增殖途径，以确定如何HB-EGF 调节基质细胞增殖，HB-EGF本身是如何调节的， 这条通路，以及其他蛋白质对基质细胞 增殖 具体目标2将确定扩散的步骤 通过阻断特异性的 子宫基质细胞周期的各个阶段。具体目标3将测试一个 模拟体内增殖途径并鉴定其他蛋白质 治疗干预的目标。 由此产生的模型 子宫基质细胞增殖的分子途径， 蜕膜化将为发育提供基本基础， 选择性的，有针对性的，治疗子宫疾病的方法， 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.