Project 2: Molecular and Functional Crosstalk of Progesterone Receptor

子宫肌瘤，或称肌瘤，是女性最常见的盆腔肿瘤。总体上发生了 肌瘤的发病率可能高达70%-75%，而女性有症状的肌瘤的比例从 25%-60%。然而，可用于肌瘤的治疗在很大程度上是由于这样一个事实： 调控这些肿瘤的发展和生长的机制仍然不清楚。二 平滑肌瘤的基本特征是平滑肌细胞增殖增加和过度 细胞外基质(ECM)沉积。因此，肌瘤表现出与其他纤维性肌瘤相似的特征 瘢痕疙瘩和肾脏纤维化等疾病。细胞外基质蛋白，特别是胶原蛋白的产生的变化， 使平滑肌细胞或成纤维细胞的增殖和分化发生深刻变化。近期 研究表明，胶原蛋白可以与各种生长因子协同作用，调节细胞的增殖 这些细胞。我们推测，肌瘤细胞的增殖增加是由于一个主要的 细胞外基质环境的改变是由于这些细胞合成新的单体胶原增加所致。我们 此外，假设抑制胶原生成的抗纤维化药物可能是有效的治疗方法 肌瘤。这项建议的具体目标是：1)确定胶原蛋白的变化 子宫肌瘤SMC通过改变生长因子之间的相互作用调节细胞增殖 受体和整合素。我们的目标是确定抗纤维化药物的抗增殖作用是否 依赖于新合成的胶原蛋白的减少以及这是否改变了酪氨酸激酶受体 信号；2)确定肌瘤SMC产生胶原的变化是否调节 这些细胞在细胞周期中的进展，并通过阻断AKT信号诱导细胞凋亡 路径。将使用siRNA和腺病毒感染方法来解决这一问题，以阻断 AICT信号转导途径；3)测定抗肝纤维化药物常青藤酮的疗效 对于肌瘤的活体动物模型，Eker大鼠。 相关性(请参阅说明)： 拟议的研究结果将为细胞外基质的变化提供新的见解 环境通过调节细胞增殖或细胞死亡促进肌瘤的生长。 最重要的是，这些研究将具有重要的临床意义，因为它们可能导致确定 一组新的治疗子宫肌瘤的潜在药物。

Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women. The overall incidenced of leiomyomas may be as high as 70-75% while the rate of symptomatic leiomyomas in women ranges from 25-60%. However, available treatments for leiomyomas are limited due in large part to the fact that the mechanisms regulating the development and growth of these tumors are still not well understood. Two essential features of leiomyoma tumors are an increase in smooth muscle cell proliferation and excessive extracellular matrix (ECM) deposition. Thus leiomyomas display characteristics similar to other fibrotic diseases such as keloids and renal fibrosis. Changes in production of ECM proteins, particularly collagen, cause profound changes in proliferation and differentiation of smooth muscle cells or fibroblast cells. Recent studies have shown that collagen can act in concert with various growth factors to regulate proliferation of these cells. We hypothesize that the increased proliferation exhibited by leiomyoma cells is due to a major shift in the ECM environment caused by increased synthesis of new, monomeric collagen by these cells. We also hypothesize the antifibrotic drugs that inhibit collagen production may be effective treatments for leiomyomas. The specific aims of this proposal are: 1) To determine whether changes in collagen production by leiomyoma SMCs regulate proliferation by altering interactions between growth factor receptors and integrins. Our goal is to determine whether the antiproliferative effect of antifibrotic drugs is dependent on a decrease in newly synthesized collagen and whether this alters tyrosine kinase receptor signaling; 2) To determine whether alterations in collagen production by leiomyoma SMCs regulate progression of these cells through the cell cycle and induce apoptosis by blocking the AKT signaling pathway. This will be addressed using siRNA and adenoviral infection approaches to block components of the AICT signaling pathway; 3) To determinen the efficacy of the antifibrotic drug halofuginone as a treatment for leiomyomas in an in vivo animal model for leiomyomas, the Eker rat. RELEVANCE (See instmctions): The results of the proposed studies will provide new insights into how changes in the extracellular matrix environment contribute to the growth of leiomyomas through regulation of cell proliferation or cell death. Most importantly, these studies will have significant clinical relevance as they may lead to the identification of a new group of drugs as potential therapeutic agents for treatment of leiomyomas.