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: 7662788
• 负责人: Kurt R. Stenmark
• 金额: $ 38.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/7662788
• 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; Hormones; Hypercapnic respiratory failure; Hypoxia; In Vitro; Inflammatory; Lead; Link; Lung; Mediating; Modeling; Molecular Models; Morbidity - disease rate; Mus; Myosin ATPase; Nuclear; 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.

该项目的目标是了解驱动转录因子下调的机制， 肺动脉高压 (PH) 中的 CREB ​​以及该事件对肺动脉 (PA) 的影响 重塑。我们之前已经证明平滑肌细胞 (SMC) 中的 CREB ​​水平降低 来自重塑的高血压 PA。抑制 SMC 中的 CREB ​​会增加其增殖、迁移和 胶原蛋白和弹性蛋白的产生。 PDGF 刺激 SMC 中 CREB ​​的丢失，从而诱导蛋白酶体 CREB ​​的降解。最后，罗格列酮 (ROSI) 可以防止 PA 壁重塑 慢性缺氧。新的初步数据将这些观察结果连接成一个一致的模型，用于监管 平滑肌细胞表型。首先，PDGF 诱导的 SMC 中 CREB ​​耗竭是由酪蛋白激酶 2 (CK2) 介导的。 其次，ROSI 通过阻断 PDGF 诱导 CK2 来防止 CREB ​​耗竭。三、PA改造是 与 PA 外膜中巨噬细胞的出现有关。这些细胞的积累是 被 ROSI 阻断，这也会减弱慢性缺氧引起的 PA 重塑。四、耗尽 CREB ​​增强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，我们假设存在级联监管，其中 PDGF 通过增加 CK2 的表达来引起 CREB ​​的消耗。 SMC 中 CREB ​​的丢失导致 SMC 增殖、胶原蛋白和弹性蛋白合成，并降低 SMC 标志物表达。 CREB ​​丢失 它还促进巨噬细胞向 PA 壁募集，从而加剧 PA 重塑。罗西 通过阻止 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。目标 1 将测试 SMC 丧失 CREB ​​是否与 PH 的发展有机械联系 在动物中。目标 2 将检查 ROSI 是否通过核受体调节 SMC 中的 CREB ​​和 CK2， PPARγ。目标 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，目标4将检查ROSI或巨噬细胞的能力 耗竭抑制 SMC CREB ​​功能丧失小鼠中 PA 重塑和 PH 的发展。 相关性（参见说明）： 尽管心肺疾病的治疗取得了重大进展，但缺氧引起的肺疾病 高血压（PH）仍然是一种致命的疾病，目前的治疗方法基本上对它没有反应。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 发病机制的贡献。