Deciphering a novel kinase function for adck2 in the heart

破译心脏中 adck2 的新激酶功能

• 批准号: 10664070
• 负责人: Priscila Sato
• 金额: $ 3.97万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10664070
• 关键词: Adenosine Triphosphate; Adult; Affect; Amino Acids; Anabolism; Bacteria; Binding; Biochemical; Biological; Blood; Branched-Chain Amino Acids; Cardiac; Cardiac Myocytes; Cause of Death; Cell Survival; Cell physiology; Cellular Structures; Cerebellar Ataxia; Complex; Data; Development; Echocardiography; Electron Transport; Electrons; Eukaryota; Family; Fatty Acids; Future; Gene Family; Generations; Genomics; Genus Hippocampus; Glucose; Goals; Heart; Heart Diseases; Heart failure; Homologous Gene; Human; Human Genome; Human body; Impairment; In Vitro; Intervention; Investigation; Ketone Bodies; Knock-out; Knockout Mice; Knowledge; Link; Lipids; Measures; Mechanics; Membrane; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Molecular; Muscle Cells; Mutation; Myocardial; Myocardium; Organ; Organelles; Oxygen Consumption; Palmitates; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Physiology; Pilot Projects; Positioning Attribute; Production; Protein Family; Protein Kinase; Proteins; Proteomics; Protons; Pump; Regulation; Research; Respiration; Role; Signal Transduction; System; Testing; Tissues; Ubiquinone; Ubiquinone Biosynthesis Pathway; Work; blood pump; branched chain fatty acid; fatty acid oxidation; heart cell; in vivo; mechanical force; member; mouse model; novel; overexpression; oxidation; pharmacologic; response; tool

Project Summary Heart failure (HF) is a leading cause of death in the world characterized by progressive heart disease that affects the pumping action of the heart muscle. As the heart is a mechanical pump solely responsible to distribute oxygenated blood to peripheral organs, discovering novel mechanisms that allow for this highly energetic organ to fulfill its function is vital for understanding basic molecular and cellular mechanisms and physiology in heart cells in normal and pathologic conditions. Mitochondria are the main drivers for ATP generation, thus these cellular structures set the energetic potential of heart cells to ultimate supply the demand for contractile generation. ADCK2, is an uncharacterized aarF domain containing kinase 2, highly expressed in the heart. Computationally, it has been predicted to enable ATP binding activity and be involved in ubiquinone biosynthesis (coenzyme Q). In addition, STRING interaction network analysis positions ADCK2 as an interactor with scl25a5 (ANT2) and TIMM13 (a member of the mitochondrial transport system). While computational evidence points to an important role for this kinase in the heart, little is known about this kinase. This project aims at filling in this gap in knowledge. We hypothesize that indeed ADCK2 is important for cardiac mitochondrial function in the adult heart, particularly involving the potential role in CoQ and electron transport chain function. Data originated from this project will serve as the basis for expansion into other larger studies. Two main aims are proposed in this relatively small study: 1) Determining the role of ADCK2 in mitochondrial respiration and adult cardiomyocyte substrate utilization; 2) Exploring how loss of ADCK2 in the heart alter ATP generation and cell survival. The overarching goal of this project is to generate tools and initial data that will engage future studies on this unexplored yet promising kinase.

项目摘要 心力衰竭（HF）是世界上主要的死亡原因，其特征在于影响心脏功能的进行性心脏病。 心肌的泵血作用。因为心脏是一个机械泵， 氧合血液到外周器官，发现新的机制，使这个高能量的器官 实现其功能对于理解心脏的基本分子和细胞机制以及生理学至关重要 正常和病理条件下的细胞。线粒体是ATP生成的主要驱动力，因此这些 细胞结构决定了心脏细胞的能量潜力，以最终满足收缩的需求。 一代ADCK 2是一种未表征的含有aarF结构域的激酶2，在心脏中高度表达。 在计算上，它已被预测，使ATP结合活性，并参与泛醌生物合成 （辅酶Q）。此外，STRING相互作用网络分析将ADCK 2定位为与scl 25 a5的相互作用物 （ANT 2）和TIMM 13（线粒体转运系统的成员）。虽然计算证据表明 这种激酶在心脏中的重要作用，但对这种激酶知之甚少。本项目旨在填补这一 知识的差距。我们假设ADCK 2确实对成人心肌线粒体功能很重要， 心脏，特别是涉及辅酶Q和电子传递链功能的潜在作用。数据源自 该项目将作为扩展到其他更大规模研究的基础。本报告提出了两个主要目标 相对较小的研究：1）确定ADCK 2在线粒体呼吸和成体心肌细胞中的作用 底物利用; 2）探索心脏中ADCK 2的损失如何改变ATP生成和细胞存活。的 该项目的总体目标是生成工具和初始数据，用于未来的研究。 尚未开发但有前途的激酶。