Perinatal Pulmonary Hypertension: Developmental Mediators

围产期肺动脉高压：发育调节因素

基本信息

批准号：
8069247
负责人：
JEFFREY R FINEMAN
金额：
$ 56.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2013-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069247
关键词：
Adipose tissue Affect Age Agonist Anatomy Animal Model Attenuated Bioavailable Biochemical Birth Blood Blood Circulation Blood Vessels Blood flow Cell Culture Techniques Child Chronic Clinical Congenital Heart Defects Data Development Disease Endothelial Cells Endothelium Etiology Event Exposure to Family Foundations Functional disorder Human Hydrogen Peroxide In Vitro Infant Investigation Ligands Liquid substance Lung Mechanics Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate NADP NADPH Oxidase Nitric Oxide Nitric Oxide Synthase Nuclear Hormone Receptors Outcome Oxidative Stress Pathologic Pathology Patients Perinatal Pulmonary Hypertension Peroxisome Proliferator-Activated Receptors Peroxonitrite Physiological Process Production Proteins Pulmonary Hypertension Pulmonary artery structure Quality of life Reaction Reactive Oxygen Species Relaxation Role SRC gene Secondary to Series Shunt Device Signal Transduction Structure of parenchyma of lung Superoxides Techniques Testing Therapeutic Translating Vascular Diseases Vascular Endothelium Vascular Graft Vascular remodeling Vulnerable Populations Zinc Fingers catalase cell type clinically relevant constriction hemodynamics human NOS3 protein improved in utero in vivo inhibitor/antagonist lung Kruppel-like factor member mortality novel pressure prevent public health relevance pulmonary artery endothelial cell research study shear stress tetrahydrobiopterin vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Abnormal pulmonary vascular relaxation and increased reactivity, early manifestations of pulmonary vascular disease, are responsible for significant morbidity in infants and children with common congenital heart defects that cause increased pulmonary blood flow. Beginning immediately after birth, the pulmonary vasculature in these patients is subjected to pathologic mechanical forces, including chronically increased shear stress, which results in early functional abnormalities of the vascular endothelium. Importantly, these functional abnormalities, which are thought to include decreases in bioavailable nitric oxide (NO) and increases in oxidative stress, occur prior to the development of well-described vascular remodeling. Unfortunately, little is known about the molecular mechanisms that mediate this process, particularly those that transduce the abnormal shear forces associated with increased pulmonary blood flow into abnormal vascular function and reactivity. Peroxisome proliferator-activated receptors (PPARs), members of a nuclear hormone receptor superfamily, are emerging as integral mediators of a wide array of disease processes, including vascular disorders. In fact, a recent study found that PPAR?, a member of the PPAR family, is decreased in patients with severe pulmonary hypertension and that shear stress decreases endothelial cell PPAR? expression. Interestingly, Kruppel-like Factor 2 (KLF2), a zinc finger protein transcriptional factor, was recently shown to be uniquely induced by flow in human lung endothelial cells, and to be a potent inhibitor of PPAR? expression in adipose tissues. However, the mechanisms by which PPAR3 and KLF2 may affect the development of pulmonary vascular disease are not understood. Utilizing our ovine model of a congenital heart defect with increased pulmonary blood flow, created by the in utero placement of an aorto-pulmonary vascular graft, we have generated preliminary data to support our overall hypothesis that disruption of PPAR? signaling secondary to a H2O2-induced, flow-mediated activation of LKLF2, results in increased ROS and decreased bioavailable NO, and thereby fundamentally participates in the development of pulmonary vascular disease under conditions of increased pulmonary blood flow. In this proposal, a series of studies that integrate anatomic, biochemical, cellular, and molecular techniques, will be undertaken in order to investigate this hypothesis. With a clinically relevant large animal model as a foundation, the data generated from this proposal could translate readily into novel and efficacious clinical therapies for patients suffering from pulmonary vascular disease. PUBLIC HEALTH RELEVANCE: Infants and children afflicted with congenital heart defects with increased pulmonary blood flow, suffer morbidity and mortality from the development of pulmonary vascular disease with abnormal pulmonary vascular reactivity. Understanding the controlling mechanisms of this pathology might improve the clinical outcome, that is the quality of life and survival, of this vulnerable population. In this proposal, we will study the novel potential role of LKLF2 and PPAR? in this pathology. With a clinically relevant large animal model as a foundation, the data generated from this proposal could translate readily into novel and efficacious clinical therapies for patients suffering from pulmonary vascular disease.

描述（由申请人提供）：异常的肺血管松弛和反应性增加，肺血管疾病的早期表现，负责在婴儿和常见的先天性心脏缺陷的儿童中显着发病，导致肺部血流增加。从出生后立即开始，这些患者的肺血管受到病理机械力，包括长期增加的剪切应力，从而导致血管内皮的早期功能异常。重要的是，这些功能异常被认为包括生物利用一氧化氮（NO）的减少和氧化应激的增加，发生在开发良好描述的血管重塑之前。不幸的是，对介导该过程的分子机制知之甚少，尤其是那些转导与肺血流增加到异常血管功能和反应性相关的异常剪切力的过程。过氧化物酶体增殖物激活的受体（PPARS）是核激素受体超家族的成员，正在成为包括血管疾病在内的广泛疾病过程的整体介体。实际上，最近的一项研究发现，PPAR家族的一个成员PPAR？患有严重肺动脉高压的患者会减少，而剪切应力降低了内皮细胞PPAR？表达。有趣的是，最近证明，锌指蛋白转录因子Kruppel样因子2（KLF2）是由人类肺内皮细胞中流动诱导的，并且是PPAR的有效抑制剂？在脂肪组织中的表达。但是，尚不清楚PPAR3和KLF2可能影响肺血管疾病发展的机制。利用先天性心脏缺陷的椭圆形模型，肺部血流增加，这是由子宫内放置在主动脉肺血管移植物的位置所产生的，我们已经产生了初步数据来支持我们的总体假设，即破坏PPAR？继发于H2O2诱导的，流介导的LKLF2激活的信号导致ROS增加并减少生物利用NO，从而从根本上参与肺血流增加的肺血管疾病的发展。在该提案中，将进行一系列整合解剖，生化，细胞和分子技术的研究，以研究这一假设。以临床相关的大型动物模型为基础，该提案产生的数据可以轻松转化为患有肺血管疾病的患者的新型有效的临床疗法。公共卫生相关性：患有先天性心脏缺陷的婴儿和儿童因肺血管疾病的发展而遭受肺血液流量增加，发病率和死亡率，并具有异常的肺血管反应性。了解这种病理的控制机制可能会改善临床结果，即这种脆弱人群的生活质量和生存质量。在此提案中，我们将研究LKLF2和PPAR的新型潜在作用？在这种病理中。以临床相关的大型动物模型为基础，该提案产生的数据可以轻松转化为患有肺血管疾病的患者的新型有效的临床疗法。