Role of the Fibrocyte in Hypoxia Induced Pulmonary Vascular Remodeling and Stiffe

纤维细胞在缺氧诱导的肺血管重塑和僵硬中的作用

• 批准号: 8502282
• 负责人: Kurt R. Stenmark
• 金额: $ 37.16万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502282
• 关键词: 1-Phosphatidylinositol 3-Kinase; 2,4-thiazolidinedione; Alveolar; Animals; Appearance; Arteries; Attenuated; Binding; Blood Vessels; Cardiopulmonary; Cell Adhesion Molecules; Cell Proliferation; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Collagen; Cyclic AMP-Responsive DNA-Binding Protein; Data; Death Rate; Development; Disease; Disease Progression; Down-Regulation; Elastin; Event; Fibronectins; Gene Expression; Genes; Goals; Homing; Hypercapnic respiratory failure; Hypoxia; In Vitro; Inflammatory; Lead; Link; Lung; Mediating; Modeling; Molecular Models; Morbidity - disease rate; Mus; Myosin ATPase; Nuclear Hormone Receptors; Nuclear Receptors; PPAR gamma; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Platelet-Derived Growth Factor; Polyubiquitination; Principal Investigator; Production; Proto-Oncogene Proteins c-akt; Publishing; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary artery structure; Regulation; Reporting; Role; Serine; Signal Transduction; Sleep; Smooth Muscle Myocytes; Testing; Thiazolidinediones; Treatment Protocols; Tunica Adventitia; Tunica Media; Up-Regulation; Vascular remodeling; calponin; casein kinase II; cytokine; diabetic; innovation; loss of function; macrophage; migration; molecular modeling; monocyte; mortality; novel; overexpression; platelet-derived growth factor BB; prevent; promoter; protective effect; protein degradation; protein expression; receptor; research study; response; rosiglitazone; transcription factor

The goal of this project is to understandthe mechanisms that drive downregulation of the transcription factor, CREB in pulmonary hypertension (PH) and the contribution of this event to pulmonary artery (PA) remodeling. We have previously shown that CREB levels are diminished in smooth muscle cells (SMCs) from remodeled, hypertensive PAs. Inhibition of CREB in SMCs increased their proliferation, migration, and collagen and elastin production. Loss of CREB in SMCs is stimulated by PDGF, which induces proteasomal degradation of CREB. Finally, rosiglitazone (ROSI) prevents remodeling of the PA wall in response to chronic hypoxia. New preliminary data links these observations into a coherent model for the regulation of SMC phenotype. First, PDGF-induced CREB depletion in SMCs is mediated by casein kinase 2 (CK2). Second, ROSI prevents CREB depletion by blocking PDGF induction of CK2. Third, PA remodeling is associated with the appearance macrophages in the PA adventitia. The accumulation of these cells is blocked by ROSI, which also attenuate PA remodeling in response to chronic hypoxia. Fourth, depletion of CREB augments the expression of adhesion molecules and cytokines linked to the accumulation of macrophages in systemic arteries. Therefore we hypothesize the existence of a regulatory cascade in which PDGF elicits the depletion of CREB via increased expression of CK2. Loss of CREB in SMCs results in SMC proliferation, collagen and elastin synthesis, and decreased SMC marker expression. Loss of CREB also promotes the recruitment of macrophages to the PA wall, which exacerbates PA remodeling. ROSI inhibits this cascade by preventing PDGF-induced CK2 expression. Four specific aims will test these hypotheses. Aim 1 will test whether SMC loss of CREB is mechanistically linked to the development of PH in animals. Aim 2 will examine whether ROSI regulates CREB and CK2 in SMCs via the nuclear receptor, PPARy. Aim 3 will determine whether downregulation of CK2 and upregulation of CREB mediate the protective effects of ROSI on SMC phenotype. Finally, Aim 4 will examine the ability of ROSI or macrophage depletion to suppress PA remodeling and the development of PH in SMC CREB loss-of-funotion mice. RELEVANCE (Seeinstructions): Despite major advances in the treatment of cardiopulmonary conditions, hypoxia-induced pulmonary hypertension (PH) remains a deadly disease that is largely unresponsive to current treatments. In order to generate innovative treatments it is critical to understand the mechanisms that lead to disease progression. This project will identify novel pathways and their contributions to the pathogenesis of PH.

该项目的目的是了解驱动转录因子下调的机制， 肺动脉高压（pH）中的CREB和该事件对肺动脉的贡献（PA） 重塑。我们以前已经表明，平滑肌细胞（SMC）中的CREB水平降低 来自重塑的高血压PA。 SMC中CREB的抑制增加了它们的增殖，迁移和 胶原蛋白和弹性蛋白生产。 PDGF刺激了SMC中CREB的损失，PDGF诱导蛋​​白酶体 Creb的退化。最后，罗西列酮（Rosi）防止对PA壁的重塑。 慢性缺氧。新的初步数据将这些观察结果链接到一个连贯的模型，以调节 SMC表型。首先，酪蛋白激酶2（CK2）介导PDGF诱导的SMC中的CREB耗竭。 其次，Rosi通过阻止CK2的PDGF诱导来防止CREB耗竭。第三，PA重塑是 与PA Adventitia中的外观巨噬细胞有关。这些细胞的积累是 被Rosi阻塞，Rosi也会响应慢性缺氧而减弱PA重塑。第四，耗尽 CREB增强了与积累相关的粘附分子和细胞因子的表达 全身动脉中的巨噬细胞。因此，我们假设存在监管级联的存在 PDGF通过增加CK2的表达引起CREB的耗竭。 SMC中CREB的损失导致 SMC增殖，胶原蛋白和弹性蛋白合成以及SMC标记表达降低。损失Creb 还可以促进巨噬细胞募集到PA壁上，这加剧了PA重塑。罗西 通过防止PDGF诱导的CK2表达来抑制该级联反应。四个具体目标将测试这些 假设。 AIM 1将测试SMC的CREB是否与pH的发展有关 在动物中。 AIM 2将检查Rosi是否通过核受体调节SMC中的CREB和CK2， PPARY。 AIM 3将确定CK2的下调和CREB的上调是否介导 ROSI对SMC表型的保护作用。最后，AIM 4将检查Rosi或巨噬细胞的能力 耗尽抑制PA重塑和SMC CREB失效小鼠中pH的发展。 相关性（参见Instructions）： 尽管心肺疾病的治疗方面取得了重大进展，但缺氧诱导的肺部 高血压（pH）仍然是一种致命疾病，对当前治疗基本上没有反应。为了 产生创新的治疗方法，了解导致疾病进展的机制至关重要。 该项目将确定新的途径及其对pH发病机理的贡献。