The heart failure interactome

心脏病是美国男性和女性的主要死亡原因，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 心肌收缩能力，提供不足的血液，以满足所有人的需求 器官。在心脏中，线粒体氧化磷酸化是90%的 心肌能量需求。在心力衰竭的进展中，线粒体功能障碍 已被广泛接受为适应不良重塑的关键部分。中的更改 线粒体在心力衰竭中的功能仍然很难在分子水平上定义。 包括改变的蛋白质水平、构象和蛋白质之间的相互作用。中的高程 先前发现由心脏超负荷引起的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 线粒体通透性调节剂使孔道对应激反应敏感。大规模 定量相互作用组学分析可以揭示蛋白质的构象和相互作用 变化涉及到心力衰竭，并提供了新的靶点，可以在 心力衰竭模型中的心肌肥大和功能障碍。该项目将开发等压物 定量蛋白质相互作用报告(IqPIR)技术及其在研究中的应用 心力衰竭中线粒体蛋白的相互作用和构象调节。此外, 将建立iqPIR交联肽的平行反应监测分析方法，以产生 用于量化蛋白质相互作用和构象特征的通用方法 任何未来的线粒体研究。

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.