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）是世界上死亡的主要原因，其特征是影响性心脏病 心肌的抽水动作。因为心脏是一个无需分发的机械泵 氧化血向外围器官，发现了允许这种高能器官的新机制 履行其功能对于理解心脏中的基本分子和细胞机制和生理学至关重要 在正常和病理条件下的细胞。线粒体是ATP生成的主要驱动因素，因此 细胞结构设定了心脏细胞的能量潜力，以最终供应收缩的需求 一代。 ADCK2是一个未表征的AARF结构域，其中包含在心脏中高度表达的激酶2。 从计算上，已经预测将启用ATP结合活性并参与泛氨基酮生物合成 （辅酶Q）。此外，字符串交互网络分析将ADCK2定位为与SCL25A5的交互器 （ANT2）和TIMM13（线粒体运输系统的成员）。而计算证据则指向 这种激酶在心脏中的重要作用，对这种激酶知之甚少。该项目旨在填补这个项目 知识差距。我们假设确实ADCK2对于成年人的心脏线粒体功能很重要 心脏，特别是涉及COQ和电子传输链功能的潜在作用。数据起源于 该项目将作为扩展到其他较大研究的基础。提出了两个主要目标 相对较小的研究：1）确定ADCK2在线粒体呼吸和成人心肌细胞中的作用 底物利用； 2）探索心脏中ADCK2的损失如何改变ATP的产生和细胞存活。这 该项目的总体目标是生成工具和初始数据，以吸引未来的研究 未开发但有前途的激酶。