Cell cycle regulation of pulmonary vascular remodeling

肺血管重塑的细胞周期调控

• 批准号: 6895574
• 负责人: BRIAN W FOUTY
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895574
• 关键词: G protein; HMG coA reductases; biological signal transduction; cAMP response element binding protein; cell cycle proteins; cell growth regulation; cell proliferation; cyclin dependent kinase; cyclins; endothelin; enzyme activity; genetically modified animals; guanine nucleotide binding protein; hormone receptor; hypoxia; immunoprecipitation; kinase inhibitor; laboratory mouse; laboratory rat; mitogens; muscle cells; phosphatidylinositol 3 kinase; prostacyclins; pulmonary artery; regeneration; tissue /cell culture; vascular smooth muscle

DESCRIPTION (provided by applicant): Vascular remodeling in pulmonary arterial hypertension (PHTN) is a heterogeneous disorder which varies depending upon the type of injury, suggesting that smooth muscle cells within a vessel wall respond in distinct ways to different stimuli. Our preliminary data suggests that the medial thickening and vascular remodeling associated with PHTN does not result from a uniform proliferation of all smooth muscle cells within the pulmonary vessel, but from selective activation of subsets of pulmonary artery smooth muscle cells (PA SMC). Since the cause of PHTN can vary between individuals, understanding how subtypes of PA SMC respond to different types of injury has potential therapeutic implication. We hypothesize that subsets of PA SMC, identified by their ability to escape G0/G1 arrest following vascular injury, are responsible for the vessel remodeling in PHTN. Using cell culture, organ culture of extra-lobar and resistance pulmonary vessels, and in vivo experiments from both wild type and cyclin-dependent kinase inhibitor- (p21Cip1/Waf1 and p27Kip1) deficient animals we will examine: 1) how G1 cell cycle proteins are regulated in 'proliferative' compared to 'non-proliferative' PA SMC following stimulation, 2) the role of 3 intracellular signaling pathways which target G1 cell cycle proteins (RhoA/Rho kinase, P(3) kinase/AKT, and CREB) on regulating PA SMC proliferation within these subtypes, and 3) the effectiveness of three clinically relevant therapies (prostacyclin, endothelin blockers, and HMG CoA reductase inhibitors (statins)) in controlling proliferation in these subset(s) of PA SMC following injury. We anticipate that at the conclusion of this proposal we will have identified how subsets of PA SMC are selectively induced to proliferate in response to vascular injury. This information may lead to more targeted therapy for the treatment of PHTN.

描述（由申请人提供）：肺动脉高压（PHTN）中的血管重塑是一种异质性疾病，取决于损伤的类型，表明容器壁中的平滑肌细胞以不同的方式对不同的刺激作出反应。我们的初步数据表明，与PHTN相关的内侧增厚和血管重塑并不是由于肺部容器中所有平滑肌细胞的均匀增殖而导致的，而是由于肺动脉平滑肌细胞亚群的选择性激活（PA SMC）。由于PHTN的原因可能在个体之间有所不同，因此了解PA SMC的亚型如何应对不同类型的损伤具有潜在的治疗意义。 我们假设PA SMC的子集通过其在血管损伤后逃脱G0/G1停滞的能力确定，是PHTN中的血管重塑。使用细胞培养，超叶和耐药性肺血管的器官培养以及来自野生型和依赖细胞周期蛋白依赖性激酶抑制剂的体内实验 - （p21CIP1/WAF1/waf1和p27kip1）缺乏动物，我们将检查：1）如何调节G1细胞周期蛋白在“相比'相比'相比'相比'相比， intracellular signaling pathways which target G1 cell cycle proteins (RhoA/Rho kinase, P(3) kinase/AKT, and CREB) on regulating PA SMC proliferation within these subtypes, and 3) the effectiveness of three clinically relevant therapies (prostacyclin, endothelin blockers, and HMG CoA reductase inhibitors (statins)) in controlling proliferation in these受伤后PA SMC的子集。 我们预计，在该提案的结论下，我们将确定如何选择性地诱导PA SMC的亚集对血管损伤的响应。该信息可能会导致更具针对性的治疗PHTN治疗。