Cell cycle regulation of pulmonary vascular remodeling

肺血管重塑的细胞周期调控

基本信息

批准号：
7230505
负责人：
BRIAN W FOUTY
金额：
$ 34.61万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230505
关键词：
1-Phosphatidylinositol 3-Kinase Adult Animals Appetite Depressants Arteries Blood Vessels Blood flow CDKN1A gene CREB1 gene Cell Cycle Cell Cycle Proteins Cell Cycle Regulation Cell Proliferation Cell division Cells Cessation of life Chronic Collagen Conflict (Psychology)Cues Cultured Cells Cyclin A Cyclin D1 Cyclin E Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins Data Disease Down-Regulation Effectiveness Elevation Endothelin Environment Epoprostenol Exhibits Exposure to G Cells G1 Arrest Goals Growth Factor Histology Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hydroxymethylglutaryl-CoA reductase Hypoxia In Vitro Individual Injury Lead Lesion Link Lobar Location Lung Mechanical ventilation Medial Mitogens Monocrotaline Morphology Organ Culture Techniques Pathologic Pathway interactions Pharmaceutical Preparations Phase Phenotype Phosphotransferases Plant alkaloid Proliferating Prostaglandins I Publishing Pulmonary Circulation Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Pulmonary vessels Purpose Reporting Resistance Retinoblastoma Rho-associated kinase Right Ventricular Hypertrophy Role Severities Signal Pathway Signal Transduction Smooth Muscle Myocytes Stimulus Sum Testing Therapeutic Up-Regulation Vascular Diseases Vascular remodeling Work base bosentan clinically relevant concept cyclin-dependent kinase inhibitor 1B extracellular in vivo inhibitor/antagonist mouse Smc1l1 protein mouse Smc1l2 protein numb protein oncoprotein p21 p27 Cell Cycle Protein p27 Enzyme Inhibitor programs pulmonary arterial hypertension receptor research study response response to injury rho

项目摘要

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，其根据损伤类型而变化，表明血管壁内的平滑肌细胞以不同的方式对不同的刺激做出反应。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肺血管内所有平滑肌细胞均匀增殖的结果，而是肺动脉平滑肌细胞 (PA SMC) 亚群选择性激活的结果。由于 PHTN 的病因因人而异，了解 PA SMC 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避 G0/G1 停滞的能力来识别）负责 PHTN 中的血管重塑。使用细胞培养、肺叶外和阻力肺血管的器官培养，以及来自野生型和细胞周期蛋白依赖性激酶抑制剂（p21Cip1/Waf1 和 p27Kip1）缺陷动物的体内实验，我们将检查：1）G1 细胞周期蛋白如何与“非增殖”PA SMC 刺激后相比，在“增殖”中受到调节，2) 3 条针对 G1 细胞周期的细胞内信号传导途径的作用蛋白质（RhoA/Rho 激酶、P(3) 激酶/AKT 和 CREB）对这些亚型内调节 PA SMC 增殖的作用，以及 3) 三种临床相关疗法（前列环素、内皮素阻滞剂和 HMG CoA 还原酶抑制剂（他汀类药物）的有效性)) 控制损伤后 PA SMC 亚群的增殖。我们预计，在本提案结束时，我们将确定如何选择性诱导 PA SMC 子集响应血管损伤而增殖。这些信息可能会导致针对 PHTN 的治疗更有针对性。