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

这个项目的目标是了解驱动转录因子下调的机制， CREB在肺动脉高压中的作用及其对肺动脉的影响 改建。我们先前已经证明，在平滑肌细胞(SMC)中CREB水平降低 来自改建的高血压PAS。抑制SMC中CREB的表达可增加其增殖、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)可防止动脉壁重塑 慢性缺氧。新的初步数据将这些观察结果联系到一个连贯的模型中，用于调节 SMC表型。首先，PDGF诱导的SMC CREB耗竭是由酪蛋白激酶2(CK2)介导的。 第二，ROSI通过阻断PDGF对CK2的诱导来防止CREB的耗竭。第三，PA重塑是 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，ROSI也减弱了对慢性低氧的PA重塑。第四，资源枯竭 CREB增强黏附分子和细胞因子的表达，这些分子和细胞因子与 体循环动脉内的巨噬细胞。因此，我们假设存在一个监管级联，其中 PDGF通过增加CK2的表达导致CREB的耗竭。CREB在SMCS中的损失导致 SMC增殖、胶原和弹性蛋白合成减少，SMC标志物表达减少。失去CREB 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表达来抑制这一级联反应。四个具体的目标将检验这些 假设。Aim 1将测试SMC中CREB的丢失是否与PH的发生有机械联系 在动物身上。目的2将研究ROSI是否通过核受体调节SMC中的CREB和CK2， Ppary.目标3将确定CK2的下调和CREB的上调是否介导了 罗西对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 耗竭以抑制SMC CREB功能丧失小鼠的PA重构和PH的发展。 相关性(请参阅说明)： 尽管在治疗心肺疾病方面取得了重大进展，但低氧诱导的肺循环 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 产生创新的治疗方法，了解导致疾病进展的机制是至关重要的。 该项目将确定新的途径及其在PH发病机制中的贡献。

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.