The heart failure interactome

心力衰竭相互作用组

• 批准号: 9816197
• 负责人: James Edward Bruce
• 金额: $ 66.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/9816197
• 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; Complex; Comprehension; Crosslinker; Cultured Cells; Development; Disease; Drug-sensitive; Female; Future; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart Mitochondria; Heart failure; Imagery; 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; Structural Protein; System; Technology; Testing; Tissue Sample; Tissues; Woman; base; crosslink; 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

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.

心脏病是美国男性和女性死亡的主要原因， 每年有90万人死亡。心力衰竭是一种复杂的疾病，其特征在于受损的 心肌收缩能力，提供不足量的血液，以满足所有的需求 机关在心脏中，线粒体氧化磷酸化是90%的 心肌能量需求在心力衰竭的发展过程中，线粒体功能障碍 已被广泛认为是适应不良性重塑的关键部分。变化 心力衰竭期间线粒体功能仍然难以在分子水平上定义 并且包括改变的蛋白质水平、构象和蛋白质-蛋白质相互作用。升高 先前发现心脏超负荷引起的NADH/NAD+比率调节线粒体 蛋白质赖氨酸乙酰化，并导致蛋白质相互作用的变化， 线粒体通透性转换孔对应激敏感的调节剂。大规模 定量相互作用组分析可以揭示蛋白质构象和相互作用 这些变化与心力衰竭有关，并提供了新的靶点，可用于缓解心力衰竭。 心力衰竭模型中的心脏肥大和功能障碍。该项目将开发等压 定量蛋白质相互作用报告（iqPIR）技术，并将其应用于研究 心力衰竭中线粒体蛋白质相互作用和构象调节。此外，本发明还提供了一种方法， 将开发用于iqPIR交联肽的平行反应监测测定，以产生 通常用于定量蛋白质相互作用和构象特征的方法， 任何线粒体研究