Proteomic signatures to identify pathways underlying the progression to heart failure

蛋白质组学特征可识别心力衰竭进展的潜在途径

• 批准号: 9973983
• 负责人: Amil M Shah
• 金额: $ 92.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973983
• 关键词: Address; Affect; Age; Atherosclerosis Risk in Communities; Biological; Biological Assay; Biological Markers; Bradykinin; Cardiac development; Cardiovascular system; Data; Databases; Development; Disease; EFRAC; Elderly; Epidemiology; Failure; Fibrosis; Frequencies; Functional disorder; Funding; Future; Genetic; Genetic Determinism; Genetic Variation; Genomics; Genotype; Goals; Heart failure; Hypertrophy; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention Studies; Left Ventricular Ejection Fraction; Lung; Mass Spectrum Analysis; Measures; Mediator of activation protein; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; Outcome; Participant; Pathway interactions; Phenotype; Physiologic pulse; Predictive Value; Prevention; Preventive Intervention; Proteins; Proteomics; Public Health; Research; Research Proposals; Risk; Risk Marker; Role; Structure; Sympathetic Nervous System; System; TNF gene; Transforming Growth Factor beta; Translating; Validation; Vascular Diseases; Visit; adjudication; aptamer; base; biracial; cardiogenesis; circulating biomarkers; cohort; defined contribution; effective intervention; effective therapy; genetic variant; genome sequencing; genomic data; heart function; human data; improved; innovation; interstitial; metabolomics; mortality; novel; novel marker; phenotypic data; precision medicine; preservation; prevent; prognostic; prospective; proteomic signature; saluretic; targeted agent; therapeutic target; translational study; whole genome

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular ejection fraction (HFpEF). Neurohormonal blockade has not proven efficacious for HFpEF, and no disease-specific therapy currently exists. There is an urgent need for novel targetable pathways, and basic/translational data implicate systemic inflammation as a potential unexploited therapeutic target, although human data is limited. The objective of this application is to define the contributions of inflammatory pathways to, and identify novel causal pathways for, the development of cardiac dysfunction and overt HF in the elderly. The central hypothesis is that specific inflammatory and neurohormonal pathways will differentially predict progressive LV dysfunction and incident HF phenotype (HFpEF vs HFrEF) in late life, and that detailed longitudinal proteomic and phenotypic data will allow for discovery of novel biologic pathways and prognostic risk markers for HF. Aptamer-based proteomics provide precise quantification of 4,931 circulating proteins and unprecedented profiling of relevant inflammatory and non-inflammatory pathways. Employing rigorous epidemiologic approaches, we will combine large-scale proteomics with detailed longitudinal cardiovascular phenotyping (echo, pulse wave velocity) and prospective HF adjudication in the largely biracial Atherosclerosis Risk in Communities (ARIC) cohort to address the following specific aims: 1) To identify individual circulating proteins and protein networks that predict incident HF and HF phenotype (HFpEF vs HFrEF); 2) To determine proteins and protein networks associated with longitudinal worsening of LV diastolic and systolic function; 3) To identify candidate proteins and protein networks most likely to be mediators of progressive LV dysfunction and HF using genomic data. The contributions of the proposed research will be to clarify the role of inflammatory – relative to neurohormonal – pathways for HF development and to discover novel mediators of HF in late life. These contributions will be significant because by determining the importance of pathways targeted by several existing agents, our findings could rapidly translate into novel preventative interventions for HF – an essential step to decrease HF-associated morbidity and mortality. This research proposal is fundamentally innovative in: (1) focusing on large-scale circulating proteomics to understand HFpEF pathobiology, with simultaneous assessment of inflammatory, neurohormonal, and novel pathways in a cohort at risk for HFpEF to prevent HF development; (2) integrating proteomic and genomic data to identify candidate proteins and pathways that are HF risk mediators as opposed to risk markers; and (3) assessing novel antecedents to HFpEF beyond hypertrophy and diastolic dysfunction, including impaired LV strain, pulmonary vascular dysfunction, and RV dysfunction. This project is expected to provide an original, integrated understanding of the biologic pathways promoting HFpEF, providing a conceptual framework for future mechanistic and translational studies of HFpEF pathobiology.

心力衰竭（HF）对老年人的影响不成比例，这些老年人主要发展HF， 心室射血分数（HFpEF）。神经激素阻滞尚未被证明对HFpEF有效， 目前存在疾病特异性治疗。迫切需要新的靶向途径， 基础/翻译数据暗示全身炎症是潜在的未开发的治疗靶点， 尽管人类数据有限。本申请的目的是定义炎症性疾病的贡献。 研究心功能不全和明显HF的发生途径，并确定其新的因果途径， 老人中心假设是，特定的炎症和神经激素途径将 差异预测晚期进行性LV功能障碍和偶发HF表型（HFpEF vs HFrEF）， 详细的纵向蛋白质组学和表型数据将允许发现新的生物学特性， HF的通路和预后风险标志物。基于适体的蛋白质组学提供了精确的定量 4，931种循环蛋白和前所未有的相关炎症和非炎症蛋白谱 途径。采用严格的流行病学方法，我们将联合收割机大规模蛋白质组学与详细的 纵向心血管表型（超声心动图、脉搏波速度）和前瞻性HF裁定， 社区中的动脉粥样硬化风险（ARIC）队列主要是为了解决以下具体目标：1） 鉴定预测偶发HF和HF表型个体循环蛋白和蛋白网络 （HFpEF与HFrEF）; 2）确定与慢性炎症纵向恶化相关的蛋白质和蛋白质网络。 LV舒张和收缩功能; 3）鉴定最有可能与LV舒张和收缩功能相关的候选蛋白和蛋白网络。 进行性LV功能障碍和HF的介质。拟议的捐助 研究将阐明炎症-相对于神经激素-通路在HF中的作用 发展和发现新的介质的HF在晚年生活。这些贡献将是巨大的，因为 通过确定几种现有药物靶向途径的重要性，我们的发现可以迅速 转化为新的HF预防干预措施-降低HF相关发病率的重要步骤 and mortality.本研究方案的创新之处在于：（1）着眼于大规模流通 蛋白质组学，以了解HFpEF病理生物学，同时评估炎症， 在HFpEF风险队列中使用神经激素和新途径预防HF发展;（2）整合 蛋白质组学和基因组学数据，以确定作为HF风险介质的候选蛋白质和途径， 与风险标志物相反;（3）评估HFpEF的新前因，而不是肥大和舒张期 肺血管功能障碍，包括受损的LV应变、肺血管功能障碍和RV功能障碍。这个项目 有望为促进HFpEF的生物学途径提供原始的、综合的理解， 为HFpEF病理生物学的未来机制和转化研究提供了概念框架。