Role of IGF axis in pulmonary hypertension

IGF轴在肺动脉高压中的作用

基本信息

批准号：
10687923
负责人：
ALLEN D EVERETT
金额：
$ 66.01万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687923
关键词：
Activities of Daily Living Address Adult Affect Age Binding Proteins Biological Biological Markers Blood Vessels Cell Proliferation Cells Cessation of life Child Childhood Clinical Clinical Data Clinical Research Code Colorado Data Development Diagnostic Disease Echocardiography Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Etiology Evaluation Exercise Test Exons Family Genes Genetic Code Genetic Variation Genomics Goals Growth Factor Growth Factor Gene Heart failure Hospitalization IGF1 gene IGF2 gene IGFBP1 gene IGFBP2 gene In Vitro Insulin-Like Growth-Factor-Binding Proteins Link Lung Lung Transplantation Mass Spectrum Analysis Measures Molecular National Heart, Lung, and Blood Institute Outcome PIK3CG gene PTEN gene Pathologic Pathway interactions Patients Phenotype Plasma Play Prognosis Prognostic Marker Proliferating Proteins Pulmonary Hypertension Quantitative Trait Loci Role SNP array SNP genotyping Sampling Sequence Analysis Serum Severities Shunt Device Signal Transduction Smooth Muscle Smooth Muscle Myocytes Somatomedins Systemic disease Testing Transplantation Universities Variant Vascular Proliferation Walking clinical care clinical practice clinically relevant cohort conventional therapy defined contribution gene network genetic association genetic variant genome wide association study hemodynamics in vivo innovation loss of function mortality new therapeutic target novel therapeutics overexpression palliative prognostic protein biomarkers pulmonary arterial hypertension pulmonary arterial pressure pulmonary artery endothelial cell pulmonary vascular cells receptor responders and non-responders response survival prediction treatment response

项目摘要

Project Summary Pulmonary arterial hypertension (PAH) in children or adults is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Pulmonary arterial smooth muscle cell (PASMC) and endothelial (PAEC) proliferation that ultimately lead to heart failure are key components of the pulmonary hypertension pathophysiologic response. Our current diagnostic/prognostic state of art (echocardiography, 6 minute walk test and NTproBNP levels) are not lung/vascular specific, have poor diagnostic correlation, confounded by systemic diseases and are not applicable to all ages. We now have pilot data that IGFBP dysregulation is a significant circulating predictor of PAH severity and survival. The overall goal of this proposal is to elucidate the in vitro and in vivo mechanistic role of IGF axis in PAH and potential as a circulating new measure of PAH therapeutic response and survival. The significance of the proposed studies is that by linking dysregulation of the IGF pathway to pulmonary endothelial/smooth muscle cellular proliferation, patient survival, and response to treatment, a critical mechanism of PAH pathobiology is revealed and provides the basis for new therapeutic, diagnostic and prognostic strategies in PAH. Using available pediatric (University of Colorado), adult (Vanderbilt) and multicenter (PAHBiobank) cohorts and isolated PAEC and PASMC from the PHBI, our overall goal will be addressed in the following specific aims: 1) Determine if IGF and IGFBPs are PAH predictors of severity, survival and response to therapy in children and adults. 2) Identify genetic variants associated with circulating levels of IGFs and IGFBPs and their relationship with clinical severity and survival. 3) Defining the contribution of the IGFBPs to the phenotypic responses of pulmonary vascular cells (PAEC and PASMC) from PAH and normal donors. If validated in this study, dysregulation of the IGF pathway could fill an important gap in clinical care and serve as a new opportunity for a more thorough understanding of PAH pathobiology and development of new therapeutic targets.

项目概要儿童或成人肺动脉高压（PAH）是一种进行性和致命性的疾病，其特征是病因不明的肺动脉压持续升高。肺动脉平滑肌细胞最终导致心力衰竭的血管平滑肌细胞 (PASMC) 和内皮细胞 (PAEC) 增殖是心力衰竭的关键组成部分。肺动脉高压的病理生理反应。我们目前的诊断/预后技术水平（超声心动图、6 分钟步行测试和 NTproBNP 水平）不是肺/血管特异性，诊断效果不佳相关性，受全身性疾病的影响，并不适用于所有年龄段。我们现在拥有的试点数据 IGFBP 失调是 PAH 严重程度和生存的重要循环预测因子。本次活动的总体目标提案旨在阐明 IGF 轴在 PAH 中的体外和体内机制作用以及作为治疗药物的潜力流行的 PAH 治疗反应和生存的新衡量标准。拟议的意义研究表明，通过将 IGF 通路的失调与肺内皮/平滑肌细胞联系起来增殖、患者生存和治疗反应，揭示了 PAH 病理学的一个关键机制并为 PAH 的新治疗、诊断和预后策略提供基础。使用可用儿科（科罗拉多大学）、成人（范德比尔特大学）和多中心（PAHBiobank）队列和孤立的 PAEC 和 PHBI 的 PASMC，我们的总体目标将通过以下具体目标来实现： 1) 确定是否 IGF 和 IGFBP 是儿童和成人 PAH 严重程度、生存率和治疗反应的预测因子。 2）识别与 IGF 和 IGFBP 循环水平相关的遗传变异及其与临床的关系严重程度和生存率。 3) 定义 IGFBP 对肺表型反应的贡献来自 PAH 和正常供体的血管细胞（PAEC 和 PASMC）。如果在本研究中得到验证，则 IGF 通路可以填补临床护理的重要空白，并为更彻底的治疗提供新的机会。了解 PAH 病理学和开发新的治疗靶点。