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The heart failure interactome

心力衰竭相互作用组

基本信息

批准号：
10218262
负责人：
James Edward Bruce
金额：
$ 66.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218262
关键词：
Acetylation Address Affect Amino Acids Binding Bioenergetics Biological Assay Biology Blood Blood Circulation Blood flow Calcium Cardiac Cause of Death Cell Line Cells Cessation of life Chemicals Chemoresistance Complex Comprehension Crosslinker Cultured Cells Development Disease Female Future Goals Heart Heart Diseases Heart Hypertrophy Heart Mitochondria Heart failure Impairment In Vitro Informatics Link Lysine Measurement Mediating Methods Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Conformation Monitor Mus Myocardial Myocardial dysfunction Myocardium NADH Organ Oxidative Phosphorylation Pathology Peptides Pharmaceutical Preparations Phenotype Protein Conformation Proteins Pump Rattus Reaction Reagent Regulation Reporter Sampling Sex Differences Signal Pathway Site Source Specificity Stable Isotope Labeling Stress System Technology Testing Tissue Sample Tissues Visualization Woman base crosslink drug-sensitive heart function human disease improved in vivo informatics tool insight isotope incorporation link protein male men mitochondrial dysfunction mitochondrial permeability transition pore next generation protein complex protein function protein protein interaction protein structure sex

项目摘要

Heart disease is the leading cause of death of both men and women in the US with more than 900,000 deaths each year. Heart failure is a complex disorder, characterized by impaired myocardium contractile ability that delivers inadequate amounts of blood to meet demands of all organs. In the heart, mitochondrial oxidative phosphorylation is the source of 90% of the myocardial energy requirement. In the progression of heart failure, mitochondrial dysfunction has become widely accepted as a key part of maladaptive remodeling. Changes in mitochondrial function during heart failure have remained difficult to define on a molecular level and include altered protein levels, conformations and protein-protein interactions. Elevation in NADH/NAD+ ratio caused by cardiac overload was previously found to regulate mitochondrial protein lysine acetylation and result in changes in protein interactions involving a primary regulator of mitochondrial permeability transition pore sensitization to stress. Large-scale quantitative interactome analysis could reveal what protein conformational and interaction changes are involved in heart failure and provide new targets that can be tested for alleviation in cardiac hypertrophy and dysfunction in heart failure models. This project will develop isobaric quantitative Protein Interaction Reporter (iqPIR) technologies and apply them to study mitochondrial protein interactions and conformational regulation in heart failure. In addition, parallel reaction monitoring assays will be developed for iqPIR cross-linked peptides to yield a generally useful method for quantification of protein interactions and conformational features in any future mitochondrial study.

在美国，心脏病是导致男性和女性死亡的主要原因