Personalized protein-protein interactomes and precision medicine in pulmonary arterial hypertension

肺动脉高压的个性化蛋白质-蛋白质相互作用组和精准医学

• 批准号: 10563134
• 负责人: Bradley Maron
• 金额: $ 41.56万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563134
• 关键词: Arterial Disorder; Binding; Biological; Biology; Blood Vessels; Cell Proliferation; Cells; Characteristics; Classification; Clinical; Clinical Management; Clinical Trials; Clinical Trials Design; Complex; Computer Models; Data; Data Set; Databases; Disease; Distal; Drug Targeting; Family member; Fibrosis; France; Genes; Genetic; Genetic Risk; Genomics; Heterogeneity; Histologic; Hypertrophy; In Situ; Individual; Inherited; Laboratories; Link; Lung; Maps; Measures; Medicine; Methods; Molecular; Molecular Profiling; Ontology; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plasma; Prognosis; Proliferating; Proteins; Proteomics; Pulmonary Heart Disease; Reporting; Resources; Selection for Treatments; Signal Pathway; Specimen; Testing; Time; Transcript; United Kingdom; Validation; Vascular Diseases; Vascular remodeling; Work; analytical method; arterial remodeling; biobank; clinical phenotype; clinical predictors; cohort; endophenotype; genetic variant; genome sequencing; health related quality of life; healthy volunteer; improved; individual patient; individualized medicine; innovation; marginalization; mortality; novel; novel strategies; overexpression; personalized strategies; phenome; point of care; precision drugs; precision medicine; precision medicine clinical trials; primary pulmonary hypertension; profiles in patients; prognostic; prognostic signature; prognostication; protein expression; protein protein interaction; pulmonary arterial hypertension; repository; response; right ventricular failure; therapeutic target; treatment response; virulence gene; whole genome

Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a highly morbid cardiopulmonary disease characterized by an obliterative vasculopathy involving distal pulmonary arterials that promotes right heart failure. Complex and integrated pathobiological signaling pathways drive vascular remodeling in PAH: the arteriopathy includes numerous endophenotypes (i.e., specific features, such as fibrosis, cellular proliferation, others) that occur to differing extent across patients. Wide variability in the proteomic and genetic profile is also observed in PAH, which accounts for phenotypic heterogeneity and inconsistent clinical response to drug therapies reported in clinical trials and at point-of-care. Overall, these observations suggest that opportunity exists to improve clinical outcome by individualizing the pathobiology-clinical phenotype relationship. Nonetheless, precision medicine in PAH remains unrealized, which we postulate is due to limitations inherent in conventional analytical methods that average biological data and overlook functionally important signaling pathways. Work from our laboratory and others has demonstrated the importance of studying functionally significant signaling pathways using network medicine to discover novel and modifiable therapeutic targets in PAH. This approach differs from classic reductionist methods that infer functionality based on transcript or protein quantity alone, which may erroneously implicate molecular bystanders in the pathogenesis of disease. However we have innovated a precision-based network medicine strategy that generates patient-specific protein-protein interaction (PPI) networks (e.g., patient-level molecular wiring map). Our approach unmasks molecular interactions that distinguish (and group together) individual patients with the same clinical phenotype. We present novel preliminary data in the accompanying application to support the central hypothesis: Developing patient- specific PPI networks will personalize clinical phenotyping and optimize prognosis in PAH. Our findings will also clarify the relationship between PAH genetic risk and pathobiology on an individual-patient level, and inform rationale and personalized drug selection using the PPI networks. To test our hypothesis, we will leverage a rich dataset from the United Kingdom PAH Phenome Biobank. This dataset includes comprehensive proteomic, genomic, clinical, and outcome data across two timepoints (1 yr apart) for idiopathic PAH, hereditary PAH, asymptomatic family members of patients with PAH, including three patients that developed PAH during the study, and healthy volunteer controls (N=500 total). The Aims are: (1) Profile patient-specific PPI networks using proteomic and genetic data, and analyze temporal differences in network features by patient group, (2) Develop, test, and validate a network score that informs phenotype and outcome of individual PAH patients. As an exploratory aim, we will use the PPI networks to predict patient-specific drug therapies. Overall, findings from this project will advance precision medicine in PAH with direct relevance to the clinical management of patients.

项目总结/文摘

项目成果

Real-world use of inhaled treprostinil for lung disease-pulmonary hypertension: A protocol for patient evaluation and prescribing.

• DOI: 10.1002/pul2.12126
• 发表时间: 2022-07
• 期刊: PULMONARY CIRCULATION
• 影响因子: 2.6
• 作者: Johnson, Shelsey W.;Finlay, Lauren;Mathai, Stephen C.;Goldstein, Ronald H.;Maron, Bradley A.
• 通讯作者: Maron, Bradley A.