Intergrated Endothelial Phenotyping to Redefine Pulmonary Hypertension

整合内皮表型重新定义肺动脉高压

基本信息

批准号：
8796036
负责人：
Jane A Leopold
金额：
$ 26.54万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-17 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8796036
关键词：
Acetylcholine Activities of Daily Living Address Agreement Bioinformatics Biological Markers Blood Vessels Blood specimen Cardiac Catheterization Procedures Cardiology Cardiopulmonary Categories Cellular biology Cessation of life Classification Clinical Clinical assessments Cluster Analysis Collaborations Cross-Sectional Studies Data Diagnostic Diagnostic Procedure Disease Disease Progression Distal Echocardiography Endothelial Cells Endothelium Etiology Exercise Exercise stress test Functional RNA Functional disorder Genetic Transcription Heart failure Image Individual Infusion procedures Lead Lung Mediating Mediator of activation protein Medical Messenger RNA Metabolic Methodology MicroRNAs Modality Modeling Molecular Molecular Biology Molecular Profiling Outcome Patients Performance Peripheral Pharmacotherapy Phase Phenotype Plasma Positron-Emission Tomography Proteomics Protocols documentation Pulmonary Hypertension Pulmonary artery structure RNA Reporting Right Ventricular Function Sampling Severity of illness Stress System Systems Biology Techniques Technology Testing Time Vascular Diseases Vascular Endothelium Vascular remodeling Vasodilation Venous Ventricular Walking abstracting aptamer arteriole base brachial artery clinically relevant design endothelial dysfunction hemodynamics hypertension control mRNA Expression multidisciplinary network architecture preclinical study premature protein function pulmonary artery endothelial cell response transcriptome sequencing transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract Pulmonary hypertension (PH) is associated with pulmonary vascular remodeling that promotes right heart failure and premature death. In PH, pulmonary endothelial dysfunction is identified as a critical mediator of aberrant distal arteriole remodeling to induce pulmonary hypertension. The current WHO classification system segregates PH patients into distinct categories based on predisposing conditions. Despite this, it remains unknown if patients within these groups share a common endothelial or endovascular pathophenotype that is a determinant of disease progression or response to pharmacotherapy. This has led to our hypothesis that an integrated pulmonary artery endothelial (patho)phenotypic analysis will identify previously unrecognized features shared between subsets of patients with PH that will inform on disease status. To address this, we propose 3 specific aims, which are designed to 1) establish an integrated pulmonary artery endothelial profile through microRNA, mRNA, and metabolyte expression analyses using RNA-Seq and proteomics; 2) evaluate the pulmonary artery endothelial response to exercise; and 3) correlate the endothelial phenotypic profile with clinical assessments of hemodynamics, right ventricular performance and functional capacity. Studies to profile the pulmonary vascular endothelium will be performed using immediately isolated pulmonary artery endothelial cells obtained at the time of right heart catheterization and plasma samples drawn in the pre- and post- exercise phases of a 6-minute walk test. Using a systems biology approach, data from the advanced phenotypic profiling studies will be incorporated into a network to uncover previously unknown interactions between microRNAs, mRNAs, and metabolic proteins that function as disease modifiers and can be developed further as targets for pharmacotherapies or biomarkers. Integrated endothelial pathophenotypic profiling will be accomplished through collaboration of a multidisciplinary team that includes individuals with expertise in pulmonary vascular disease, cardiology, imaging, cell and molecular biology, and bioinformatics. Completion of the integrated phenotyping proposal will lead to the emergence of key endothelial phenotypes that will redefine our approach to patients with PH.

描述（由申请人提供）：项目摘要/摘要肺动脉高压（pH）与肺血管重塑有关，可促进正确的心力衰竭和过早死亡。在pH中，肺内皮功能障碍被确定为远端小动脉重塑以诱导肺动脉高压的关键介质。当前的WHO分类系统将pH患者根据易感性条件分为不同的类别。尽管如此，这些组中的患者是否具有常见的内皮或血管内病理表调型，这是疾病进展或对药物治疗的反应，仍然未知。这导致了我们的假设，即综合的肺动脉内皮（PATHO）表型分析将确定先前未识别的pH患者亚群共享的特征，这将使疾病状况有助于疾病状况。为了解决这个问题，我们提出了3个特定目的，这些目标旨在1）通过microRNA，mRNA和分泌素表达分析使用RNA-Seq和蛋白质组学建立综合的肺动脉内皮谱分析； 2）评估肺部动脉内皮对运动的反应； 3）将内皮表型谱与血流动力学，右心性能和功能能力的临床评估相关联。介绍肺血管内皮的研究将使用在右心导导管插入术时获得的立即分离的肺部动脉内皮细胞和在6分钟步行试验的运动前和运动后绘制的血浆样品中获得的研究。使用系统生物学方法，将将来自高级表型分析研究的数据纳入网络中，以发现以前无知的microRNA，mRNA和代谢蛋白之间的相互作用，这些相互作用可作为疾病修饰剂，并可以进一步发展为药物治疗或生物标志物的靶标。综合的内皮病理表型分析将通过一个多学科团队的协作来完成，该团队包括具有肺血管疾病，心脏病学，成像，细胞和分子生物学以及生物信息学方面具有专业知识的人。综合表型提案的完成将导致关键内皮表型的出现，这将重新定义我们对pH患者的方法。