Reactive Oxygen Species in Vascular Disease

血管疾病中的活性氧

基本信息

批准号：
9124895
负责人：
Patrick J Pagano
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9124895
关键词：
Accounting Address Animals Attenuated Binding Biology Blood Vessels Bone Morphogenetic Proteins Cause of Death Cell Proliferation Cessation of life Clinical Cyclic AMP Data Development Diagnosis Disease Elements Endothelial Cells Failure Foundations Genetic Techniques Grant Health Heart Hypertrophy Heart failure Human Hypoxia Imaging Device In Situ Lesion Lung Mediating Mediator of activation protein Modeling Molecular Genetics Mus NADPH Oxidase Oxidants Pathologic Pathway interactions Patients Pharmacotherapy Phenotype Play Production Protein Isoforms Pulmonary Hypertension Pulmonary artery structure Pulmonary vessels Rattus Reactive Oxygen Species Research Resistance Rodent Model Role SHH gene Signal Transduction Specimen Testing Therapeutic Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular Proliferation Vascular remodeling Vascular resistance Ventricular angiogenesis base cyanine dye 5 hemodynamics human disease in vivo in vivo imaging inhibitor/antagonist innovation loss of function mouse model novel novel therapeutics pressure prevent pulmonary arterial hypertension pulmonary artery endothelial cell response

项目摘要

DESCRIPTION (provided by applicant): Right ventricular (RV) failure is the leading cause of death in patients with pulmonary arterial hypertension (PAH). Hypoxia-induced PAH is a common form of the disease leading to heart failure. A poor understanding of pathologic mechanisms presents a barrier to clinical approaches targeting the disease, which is often associated with rapid and aggressive vascular remodeling, plexiform lesion (PL) formation, and RV failure. Reactive oxygen species (ROS) from NADPH oxidases (Noxs) are implicated in PAH and previous data support a role for Nox2 in pulmonary vascular endothelial (EC) proliferation. However, despite its expression in the pulmonary vascular wall, no information exists for Nox1 in PAH. Importantly, a functional role for Nox1 in vascular wall thickening and PL formation is entirely unknown. We propose a novel role for Nox1 in promoting proliferation and vascular remodeling via Gremlin1, an antagonist of bone morphogenetic protein. This hypothesis is based on a recent association of Gremlin1 with PAH and our preliminary data supporting Nox1-mediated Gremlin1 expression in human pulmonary artery endothelial cell (HPAEC) proliferation. In fact, the role that any Nox plays in mediating upstream and downstream mediators of EC Gremlin1, including sonic hedgehog and CREB, is entirely unknown. Our previous aims led to development of a highly-selective and efficacious Nox1 inhibitor. This inhibitor, as well as other molecular genetic techniques, allows identification of multiple new pathways involving Gremlin1 in hypoxia-induced PAH. We will test the central hypothesis that Nox1 propagates Gremlin1-mediated signaling, thereby promoting hypoxia- induced PAH and RV failure. This will be tested by addressing the following aims: (1) To interrogate the expression of Nox1 and its contribution to ROS production and Gremlin1- mediated signaling in human pulmonary endothelial cell proliferation under hypoxic conditions; (2) To determine whether specific Nox1 inhibitor permeates and targets hypoxia-induced endothelial ROS signaling and Gremlin1 expression and attenuates hemodynamics in a mouse model of PAH; and (3) To determine whether aerosolization of Nox1 inhibitor prevents and/or reverses RV failure in a rat model of vascular occlusive PAH. This paradigm-shifting proposal uncovers a novel role for Gremlin1-Nox1 in PAH and RV failure. The research plan, built on compelling preliminary data, is expected to open up a new field of inquiry in vascular biology and is conceptually and technologically innovative. From a therapeutic standpoint, delivery of a novel and highly-specific Nox1 inhibitor to disrupt this pathway in the pulmonary vascular endothelium via aerosolization is expected to serve as a firm foundation for new drug therapies.

描述（由适用提供）：右心（RV）衰竭是肺动脉高压（PAH）患者的主要死亡原因。缺氧引起的PAH是导致心力衰竭的疾病的一种常见形式。对病理机制的不良理解列出了针对该疾病的临床方法的障碍，该方法通常与快速和攻击性的血管重塑，丛状病变（PL）形成和RV衰竭有关。 NADPH氧化物（NOX）的活性氧（ROS）在PAH中实施，以前的数据支持NOX2在肺血管内皮（EC）增殖中的作用。然而，它在肺血管壁中的表达，在PAH中不存在NOX1的信息。重要的是，NOX1在血管壁增厚和PL形成中的功能作用是完全未知的。我们提出了NOX1在通过Gremlin1（骨形态发生蛋白的拮抗剂）促进增殖和血管重塑中的新作用。该假设是基于Gremlin1与PAH的最新关联以及我们支持NOX1介导的Gremlin1在人肺动脉内皮细胞（HPAEC）增殖中的表达的初步数据。实际上，任何NOX在介导EC Gremlin1的上游和下游介体（包括Sonic Hedgehog and Creb）中扮演的作用是完全未知的。我们以前的目标导致了高度选择性和有效的NOX1抑制剂的发展。该抑制剂以及其他分子遗传技术允许鉴定低氧诱导的PAH中涉及Gremlin1的多种新途径。我们将测试NOX1传播Gremlin1介导的信号传导的中心假设，从而促进缺氧诱导的PAH和RV失败。这将通过解决以下目的来测试：（1）询问NOX1的表达及其对ROS产生和Gremlin1介导的信号的贡献在低氧条件下人类肺部内皮细胞增殖中的表达；（2）确定特定的NOX1抑制剂是否渗透并靶向缺氧诱导的内皮ROS信号传导和Gremlin1表达，并在PAH小鼠模型中减弱血液动力学；（3）确定NOX1抑制剂的雾化是否可以防止和/或逆转在大鼠的血管闭塞PAH模型中。该范式转移提案发现了Gremlin1-Nox1在PAH和RV失败中的新作用。该研究计划以引人注目的初步数据为基础，预计将开放一个新的血管生物学研究领域，并且在概念上是在技术上是创新的。从治疗的角度来看，新型且高度特异性的NOX1抑制剂的递送通过雾化中的肺血管内皮中破坏这种途径，预计将成为新药物疗法的牢固基础。