Role of IGF axis in pulmonary hypertension

IGF轴在肺动脉高压中的作用

• 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
• 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

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.

项目总结