Raft/Caveolar Mechanisms in Pulmonary Hypertension

肺动脉高压的筏/小窝机制

• 批准号: 7198103
• 负责人: PRAVIN B SEHGAL
• 金额: $ 33.28万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198103
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Alveolar; Angiotensin II; Autoimmune Diseases; Binding; Biological Availability; Blood Vessels; Cardiovascular system; Caveolae; Caveolins; Cell membrane; Cells; Clinical; Complex; Cultured Cells; Cytokine Signaling; Cytosol; Detergents; Development; Disruption; Dominant-Negative Mutation; Down-Regulation; Endothelial Cells; Epithelial Cells; Event; Experimental Models; Extravasation; Fibroblasts; Gene Expression; Genetic; Heat-Shock Proteins 90; Histologic; Hypertension; Inflammation; Injection of therapeutic agent; Interleukin 6 Receptor; Interleukin-6; Investigation; Localized; Location; Lung; Lung diseases; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Monocrotaline; Nitric Oxide; Organelles; Pathogenesis; Plant alkaloid; Play; Proteins; Pulmonary Hypertension; Rattus; Research Proposals; Resistance; Right Ventricular Hypertrophy; Role; STAT1 gene; STAT3 gene; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Testing; Time; Tissues; Translational Research; Up-Regulation; Vascular Endothelium; base; caveolin 1; cell injury; cell type; cellular targeting; cytokine; day; insight; molecular mass; mutant; novel; novel therapeutics; primary pulmonary hypertension; research study; transcription factor

DESCRIPTION (provided by applicant): This translational research proposal seeks to apply recent novel insights into the mechanisms of cell signaling at the level of the plasma membrane (the caveola/raft signaling hypothesis and the interleukin-6-raft-STAT3 signaling model) to an understanding of the pathogenesis of PH. Caveolin-1-containing detergent-resistant plasma membrane rafts are now recognized as specialized signaling organelles, including cytokine signaling. There is now growing evidence for a role of cytokines in the pathogenesis of lung diseases. As examples, elevated serum levels of IL-6 have been observed in primary pulmonary hypertension (PH) and in PH associated with autoimmune diseases and AIDS. In a rat model, a single injection of the plant alkaloid monocrotaline (MCI) results within 48 hrs in endothelial cell damage, membrane leakage, upregulation of IL-6 mRNA and bioactivity but a marked downregulation of caveolin-1 in the lung, followed by development of PH 10-14 days later. The focus of the proposed studies is two-pronged: (a) to evaluate the hypothesis that pulmonary endothelial-cell raft/caveolar disruption by MCT is an initiating event in the pathogenesis of PH (Specific Aim I), and (b) to investigate the function of membrane rafts and of the newly discovered cytosolic caveolin-containing Palade complexes in IL-6-induced STAT3 signaling in lung-specific cells (Specific Aims II and III). Aim I will include investigations of the time-course, histologic location, and cellular and molecular mechanisms for the downregulation of caveolin proteins and gene expression, and of the integrity of caveolar/raft function in pulmonary vascular and parenehymal tissues of MCT-treated rats. Aim II includes molecular studies of the mechanisms of association of STAT3 with caveolin-1 and of STAT3 activation in plasma membrane rafts in pulmonary endothelial cells, alveolar type II-like epithelial cells and lung fibroblasts. Aim Ill includes studies of the protein components of STAT3-containing cytosolic Palade complexes and their function in ferrying signaling molecules from the plasma membrane rafts to the cell interior. Mechanistic insights derived from this project are likely to suggest novel therapeutic approaches in the management of pulmonary hypertension. Moreover, the proposed studies are of particularly broad significance in that insights into the molecular mechanisms involved in raft-STAT signaling are likely to be applicable to cytokine-mediated activation of STAT transcription factors in perhaps all cell types, as well as to other signaling pathways localized in raft microdomains (eNOS and angiotensin II signaling).

描述（由申请人提供）： 这项转化研究计划旨在将最近对质膜水平细胞信号传导机制（小窝/筏信号传导假说和白细胞介素 6-raft-STAT3 信号传导模型）的新见解应用于了解 PH 的发病机制。含有 Caveolin-1 的耐去污剂质膜筏现在被认为是专门的信号细胞器，包括细胞因子信号传导。现在越来越多的证据表明细胞因子在肺部疾病的发病机制中发挥着作用。例如，在原发性肺动脉高压 (PH) 以及与自身免疫性疾病和艾滋病相关的 PH 中观察到 IL-6 血清水平升高。在大鼠模型中，单次注射植物生物碱野百合碱 (MCI) 在 48 小时内导致内皮细胞损伤、膜渗漏、IL-6 mRNA 和生物活性上调，但肺部的 Caveolin-1 显着下调，随后 10-14 天后出现 PH。 拟议研究的重点有两个方面：(a) 评估 MCT 导致的肺内皮细胞筏/小窝破坏是 PH 发病机制中的起始事件的假设（具体目标 I），以及 (b) 研究膜筏和新发现的含细胞质小窝蛋白的 Palade 复合物在 IL-6 诱导的 STAT3 信号传导中的功能。 肺特异性细胞（具体目标 II 和 III）。目标 I 将包括研究小窝蛋白和基因表达下调的时间过程、组织学位置、细胞和分子机制，以及 MCT 治疗大鼠肺血管和实质组织中小窝/筏功能的完整性。目标 II 包括 STAT3 与 Caveolin-1 关联机制以及肺内皮细胞、肺泡 II 型样上皮细胞和肺成纤维细胞质膜筏中 STAT3 激活机制的分子研究。 Aim Ill 包括对含有 STAT3 的胞质 Palade 复合物的蛋白质成分及其将信号分子从质膜筏运送到细胞内部的功能的研究。 从该项目中得出的机制见解可能会提出治疗肺动脉高压的新治疗方法。此外，拟议的研究具有特别广泛的意义，因为对 raft-STAT 信号传导分子机制的深入了解可能适用于细胞因子介导的 STAT 转录因子在所有细胞类型中的激活，以及位于 raft 微域中的其他信号传导途径（eNOS 和血管紧张素 II 信号传导）。

项目成果

Plasma membrane rafts and chaperones in cytokine/STAT signaling.

• DOI: 10.18388/abp.2003_3652
• 发表时间: 2003
• 期刊: Acta biochimica Polonica
• 影响因子: 1.7
• 作者: P. Sehgal

Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells.

野百合碱诱导的肺动脉内皮和肺泡上皮细胞巨细胞增多症的不一致调节变化。

• DOI: 10.1152/ajplung.00535.2005
• 发表时间: 2006
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Mukhopadhyay,Somshuvra;Sehgal,PravinB
• 通讯作者: Sehgal,PravinB

Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques.

• DOI: 10.1152/ajplung.00087.2009
• 发表时间: 2009-10
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: P. Sehgal;Somshuvra Mukhopadhyay;K. Patel;Fang Xu;S. Almodovar;R. Tuder;S. Flores