Project 2: Molecular and Functional Crosstalk of Progesterone Receptor

子宫平滑肌瘤或纤维瘤是女性盆腔最常见的肿瘤。总体发生率 平滑肌瘤可能高达70-75%，而女性中有症状的平滑肌瘤的比率范围为 25- 60%然而，平滑肌瘤的可用治疗是有限的，这在很大程度上是由于以下事实： 调节这些肿瘤的发展和生长的机制仍然没有很好的理解。两 平滑肌瘤肿瘤的基本特征是平滑肌细胞增殖的增加和过度增殖。 细胞外基质（ECM）沉积。因此，平滑肌瘤显示出与其他纤维化 瘢痕疙瘩和肾纤维化等疾病。ECM蛋白，特别是胶原蛋白的产生变化， 引起平滑肌细胞或成纤维细胞增殖和分化的深刻变化。最近 研究表明，胶原蛋白可以与各种生长因子协同作用来调节细胞的增殖， 这些细胞。我们推测平滑肌瘤细胞增殖的增加是由于 ECM环境的变化，由这些细胞增加的新的单体胶原蛋白的合成引起。我们 我还假设抑制胶原蛋白产生的抗纤维化药物可能是有效的治疗方法， 平滑肌瘤本建议的具体目的是：1）确定胶原蛋白的变化是否 平滑肌细胞通过改变生长因子之间的相互作用调节增殖 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酪氨酸激酶受体 2）为了确定平滑肌瘤SMC的胶原蛋白产生的改变是否调节 这些细胞的进程通过细胞周期和诱导凋亡通过阻断AKT信号 通路这将使用siRNA和腺病毒感染方法来阻断 AICT信号通路; 3）确定抗纤维化药物常山酮作为治疗的有效性 对于平滑肌瘤的体内动物模型Eker大鼠中的平滑肌瘤。 相关性（见说明）： 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平滑肌瘤的生长。 最重要的是，这些研究将具有显著的临床相关性，因为它们可能导致识别 作为治疗平滑肌瘤的潜在治疗剂的一组新药。

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.