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

该项目的目标是了解驱动转录因子下调的机制， CREB在肺动脉高压（PH）中的作用及其对肺动脉（PA）的影响 重塑我们以前已经表明，CREB水平减少平滑肌细胞（SMC） 重塑的高血压肺动脉抑制平滑肌细胞中的CREB可增加其增殖、迁移和增殖。 胶原蛋白和弹性蛋白的产生。SMC中CREB的缺失被PDGF刺激，其诱导蛋白酶体 CREB降解。最后，罗格列酮（ROSI）可防止PA壁的重塑， 慢性缺氧新的初步数据将这些观察结果联系到一个协调一致的模型， SMC表型。首先，PDGF诱导的SMC中CREB耗竭由酪蛋白激酶2（CK2）介导。 第二，ROSI通过阻断PDGF对CK2的诱导来防止CREB耗竭。第三，PA重塑是 与肺动脉外膜巨噬细胞的出现有关。这些细胞的积累是 通过ROSI阻断，这也减弱了响应于慢性缺氧的PA重塑。第四，损耗 CREB增强了粘附分子和细胞因子的表达， 巨噬细胞。因此，我们假设存在一个调节级联反应，其中 PDGF通过增加CK2的表达来促进CREB的消耗。SMC中CREB的缺失导致 SMC增殖、胶原和弹性蛋白合成减少，SMC标志物表达减少。CREB损失 还促进巨噬细胞向PA壁的募集，这加剧了PA重塑。Rosi 通过阻止PDGF诱导的CK2表达来抑制这种级联反应。四个具体目标将检验这些目标。 假设目的1将测试CREB的SMC损失是否与PH的发展有机械联系 在动物身上。目的2将检测ROSI是否通过核受体调节SMC中的CREB和CK 2， PPARy。目的3将确定CK2下调和CREB上调是否介导了 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， 消耗以抑制SMC CREB功能丧失小鼠中PA重塑和PH的发展。 相关性（参见说明）： 尽管在心肺疾病的治疗方面取得了重大进展，但缺氧诱导的肺动脉高压仍是一个严重的问题。 高血压（PH）仍然是一种致命的疾病，对目前的治疗基本上没有反应。为了 为了产生创新的治疗方法，理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。

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.