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: 10895160
• 负责人: Amil M Shah
• 金额: $ 76.31万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10895160
• 关键词: Address; Affect; Age; Atherosclerosis Risk in Communities; Biological; Biological Assay; Biological Markers; Bradykinin; Cardiovascular system; Data; Databases; Development; Disease; EFRAC; Elderly; Epidemiology; Ethnic Origin; 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; Mass Spectrum Analysis; Measures; Mediator; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; Outcome; Participant; Pathway interactions; Phenotype; Physiologic pulse; Predictive Value; Prevention; Proteins; Proteomics; Public Health; Research; Research Proposals; Risk; Risk Marker; Role; Structure; Sympathetic Nervous System; System; TNF gene; Transforming Growth Factor beta; Translating; Validation; Visit; adjudication; aptamer; biomarker identification; biracial; candidate identification; circulating biomarkers; cohort; defined contribution; effective intervention; effective therapy; genetic variant; genome sequencing; genomic data; heart function; human data; improved; innovation; interstitial; metabolomics; mortality; multi-ethnic; novel; novel marker; phenotypic data; precision medicine; preservation; prevent; preventive intervention; prognostic; prospective; proteomic signature; pulmonary vascular disorder; risk prediction; saluretic; systemic inflammatory response; 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) 对老年人的影响尤为严重，他们主要发生心力衰竭且左心功能保留 心室射血分数 (HFpEF) 神经激素阻断尚未被证明对 HFpEF 有效，而且没有证据表明神经激素阻断对 HFpEF 有效。 目前存在针对疾病的特异性治疗，并且迫切需要新的靶向途径。 基本/转化数据表明全身炎症是一个潜在的未开发的治疗靶点， 尽管人类数据有限，但该应用的目的是确定炎症的贡献。 心功能不全和明显心力衰竭发展的途径并确定新的因果途径 中心假设是特定的炎症和神经激素途径会影响老年人。 差异预测晚年进行性左心室功能障碍和心力衰竭表型（HFpEF 与 HFrEF）， 详细的纵向蛋白质组学和表型数据将有助于发现新的生物制剂 基于适配体的蛋白质组学为心力衰竭的通路和预后风险标记提供了精确的量化。 4,931 个循环蛋白以及前所未有的相关炎症和非炎症分析 采用严格的流行病学方法，我们将大规模蛋白质组学与详细的研究相结合。 纵向心血管表型（回声、脉搏波速度）和前瞻性 HF 判定 主要是混血社区动脉粥样硬化风险 (ARIC) 队列，旨在实现以下具体目标：1) 识别预测心力衰竭事件和心力衰竭表型的个体循环蛋白和蛋白网络 （HFpEF 与 HFrEF）；2) 确定与恶化相关的纵向蛋白质和蛋白质网络 左心室舒张和收缩功能；3) 识别最有可能的候选蛋白质和蛋白质网络 使用基因组数据研究进行性左心室功能障碍和心力衰竭的介质。 研究将阐明炎症（相对于神经激素）通路对心力衰竭的作用 这些贡献将是重要的，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 转化为心力衰竭的新型预防干预措施——降低心力衰竭相关发病率的重要步骤 该研究方案的根本创新在于：（1）关注大规模循环。 通过蛋白质组学了解 HFpEF 病理学，同时评估炎症、 (2) 在有 HFpEF 风险的人群中整合神经激素和新途径，以预防 HF 发展； 蛋白质组和基因组数据，用于识别心力衰竭风险介质的候选蛋白质和途径 与风险标记相反；(3) 评估肥厚和舒张以外的 HFpEF 的新前因 功能障碍，包括左心室应变受损、肺血管功能障碍和右心室功能障碍。 有望对促进 HFpEF 的生物途径提供原创的、综合的理解， 为 HFpEF 病理学的未来机制和转化研究提供概念框架。

项目成果

Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies.

对欧洲和非洲血统个体的血浆蛋白质组分析确定了顺式 pQTL 和蛋白质组范围关联研究的模型。

• 发表时间: 2022-05
• 影响因子: 30.8
• 作者: Zhang, Jingning;Dutta, Diptavo;Köttgen, Anna;Tin, Adrienne;Schlosser, Pascal;Grams, Morgan E;Harvey, Benjamin;CKDGen Consortium;Yu, Bing;Boerwinkle, Eric;Coresh, Josef;Chatterjee, Nilanjan
• 通讯作者: Chatterjee, Nilanjan