Project 2: Molecular and Functional Crosstalk of Progesterone Receptor

项目2：黄体酮受体的分子和功能串扰

基本信息

批准号：
7752683
负责人：
Ji-Yong Julie Kim
金额：
$ 46.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752683
关键词：
70-kDa Ribosomal Protein S6 Kinases AKT Signaling Pathway AKT inhibition Address Affect Age Angioplasty Animal Model Animal Testing Animals Apoptosis Apoptotic Architecture Benign Blood Vessels Cell Culture Techniques Cell Cycle Cell Cycle Proteins Cell Death Cell Line Cell Proliferation Cell Proliferation Regulation Cell surface Cells Characteristics Collagen Collagen Fibril Collagen Type I Complex Cyclin E Cytoplasmic Tail DNA biosynthesis Deposition Diagnosis Disease Dose Down-Regulation EGF gene Endometrium Endothelial Cells Environment Epidermal Growth Factor Receptor Event Exhibits Extracellular Domain Extracellular Matrix Extracellular Matrix Proteins Extracellular Signal Regulated Kinases Fibrillar Collagen Fibroblast Growth Factor 2 Fibroblasts Fibroid Tumor Fibronectins Fibrosis Figs - dietary Focal Adhesion Kinase 1 Goals Growth Growth Factor Growth Factor Receptors Growth and Development function Halofuginone Harvest Health Healthcare In Vitro Incidence Infection Inflammation Injury Integrins Keloid Kidney Lead Leiomyoma Length Link Liver Malignant Epithelial Cell Measures Microarray Analysis Mitogen-Activated Protein Kinases Modeling Molecular Nude Mice Pathway interactions Pelvic Neoplasms Pelvis Pharmaceutical Preparations Phase Phosphorylation Plasminogen Activator Inhibitor 1 Plastics Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Principal Investigator Production Progesterone Receptors Protein Binding Proteins Proto-Oncogene Proteins c-akt Pulmonary Fibrosis Rattus Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporting Research Signal Pathway Signal Transduction Site Small Interfering RNA Smooth Muscle Myocytes Testing Therapeutic Therapeutic Agents Time Tissues Uterine Fibroids Vascular Proliferation Woman angiogenesis bladder Carcinoma clinically relevant density effective therapy efficacy testing in vivo indexing inhibitor/antagonist insight mRNA Expression mesangial cell monomer mouse model programs receptor reproductive response to injury restenosis src-Family Kinases tumor tumor growth

项目摘要

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.

子宫平滑肌瘤或肌瘤是女性最常见的骨盆肿瘤。整体发生的平滑肌瘤可能高达70-75％ 25-60％。但是，在很大程度上，由于调节这些肿瘤的发育和生长的机制仍然不太了解。二平滑肌肿瘤的基本特征是平滑肌细胞增殖的增加和过度细胞外基质（ECM）沉积。因此，平滑肌瘤显示出类似于其他纤维化的特征诸如酮类和肾纤维化等疾病。 ECM蛋白，特别是胶原蛋白的生产变化，引起平滑肌细胞或成纤维细胞的增殖和分化的深刻变化。最近的研究表明，胶原蛋白可以与各种生长因子一起起作用，以调节这些细胞。我们假设平滑肌瘤细胞表现出的增殖增加是由于主要这些细胞对新的，单体胶原蛋白的合成增加而引起的ECM环境的变化。我们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。该提案的具体目的是：1）确定胶原蛋白的变化是否变化平滑肌瘤生产SMC通过改变生长因子之间的相互作用来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生作用是否是取决于新合成的胶原蛋白的减少以及该是否改变酪氨酸激酶受体信号传导； 2）确定平滑肌瘤的胶原蛋白产生的改变是否调节这些细胞通过细胞周期的进展，并通过阻断AKT信号传导诱导凋亡路径。这将使用siRNA和腺病毒感染方法来解决这一问题，以阻止 AICT信号通路； 3）确定抗纤维化药物halofuginone的疗效作为治疗在平滑肌瘤的体内动物模型中，Eker大鼠的平滑肌瘤。相关性（请参阅Instmctions）：拟议研究的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来促进平滑肌瘤的生长。最重要的是，这些研究将具有显着的临床相关性，因为它们可能导致鉴定一组新的药物，是治疗平滑肌瘤的潜在治疗剂。