The heart failure interactome

心力衰竭相互作用组

基本信息

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
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/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

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.

心脏病是美国男性和女性死亡的主要原因，超过每年有 90 万人死亡。心力衰竭是一种复杂的疾病，其特征是功能受损心肌收缩能力无法提供足够的血液来满足所有人的需求器官。在心脏中，线粒体氧化磷酸化是 90% 的能量来源心肌能量需求。在心力衰竭的进展中，线粒体功能障碍已被广泛认为是适应不良重塑的关键部分。变化心力衰竭期间的线粒体功能仍然难以在分子水平上定义包括改变的蛋白质水平、构象和蛋白质-蛋白质相互作用。海拔高度先前发现由心脏超负荷引起的 NADH/NAD+ 比率可以调节线粒体蛋白质赖氨酸乙酰化并导致涉及初级的蛋白质相互作用的变化线粒体通透性调节剂将孔对应激敏感。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，并提供了可以测试缓解情况的新目标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相互作用和构象调节。此外，将为 iqPIR 交联肽开发平行反应监测测定法，以产生定量蛋白质相互作用和构象特征的普遍有用的方法任何未来的线粒体研究。