FUNCTION OF HB/EGF IN UTERINE STROMAL CELLS

HB/EGF 在子宫基质细胞中的功能

• 批准号: 2669662
• 负责人: JOY I MULHOLLAND
• 金额: $ 23.84万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2669662
• 关键词: antisense nucleic acid; cell differentiation; cell proliferation; connective tissue cells; decidua; epidermal growth factor; estrogens; human tissue; laboratory rat; progesterone; protein structure function; uterus; vascular endothelial growth factors

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.

子宫功能障碍和疾病通常是由于破坏 调节细胞增殖。 作为例子，子宫内膜癌， 子宫内膜异位症和平滑肌瘤的特征是异常细胞 增殖。 另外，子宫内膜不足或异步 增殖和发育是不孕的经常原因。 如果 子宫细胞调节的细胞或组织特异性步骤 已知子宫特异性调节分子已知，可以 作为控制扩散和的靶向疗法的基础 子宫疾病的分化。 结果，副作用 可以避免目前的疗法。需要孕酮 支持增殖和分化 子宫基质细胞，但对分子知之甚少 孕酮刺激的途径，导致有丝分裂或 十字无限。 我们已经证明了肝素结合表皮 生长因子（HB-EGF）表达在孕酮中刺激 子宫基质细胞和抑制HB-EGF功能也抑制 十字无限。 因此，孕酮和HB-EGF是唯一的 被证明对 十字无限。 拟议的研究项目旨在阐明 HB-EGF调节分子途径的机制 导致子宫基质细胞增殖，并确定如何 增殖控制截然不同。 我们的项目将测试 假设cyDualizatization取决于雌激素诱导的 基质细胞增殖，由HB-EGF介导。 具体目标 1将测试假设的增殖途径，以确定HB-EGF如何 调节基质细胞增殖，如何调节HB-EGF本身 该途径以及其他蛋白质对于基质细胞至关重要 增殖。 特定的目标2将定义扩散的步骤 通过阻止特定的途径对于划定至关重要 子宫基质细胞周期的阶段。特定目标3将测试 在体内建模增殖途径，并识别其他蛋白质 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和 义词化将为发展的基础 源自子宫疾病的选择性，有针对性的疗法 不受管制的细胞增殖。