The role of purine nucleotide metabolism in cardiac decompensation and failure

嘌呤核苷酸代谢在心脏失代偿和衰竭中的作用

基本信息

批准号：
10544141
负责人：
Rachel Lopez-Schenk
金额：
$ 3.94万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544141
关键词：
5&apos -Nucleotidase AMP Deaminase ATP Hydrolysis Adenine Nucleotides Adenosine Affect Aging American Automobile Driving Basic Science Biological Assay Blood Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cell physiology Cells Chemicals Chronic Complementary DNA Complex Consumption Creatine Data Degradation Pathway Development Diagnosis Disease Drug Kinetics Echocardiography Energy Metabolism Ensure Enzymes Equilibrium Etiology Exhibits FRAP1 gene Failure Fibrosis Financial compensation Free Energy Functional disorder Gene Expression Genes Goals Harvest Heart Heart failure Housekeeping Gene Hydrolysis Impairment Kinetics Knock-out Libraries Measures Mechanics Metabolic Metabolic dysfunction Methods Modeling Molecular Target Morphology Myocardial Myocardium Nucleotides Nutrient Operative Surgical Procedures Pathologic Pathway interactions Patients Phosphocreatine Phosphorylation Physiological Play Poly(A)+ RNA Process Property Proteins Publishing Pump Purine Nucleotides Purines Rattus Role Sampling Solid Sprague-Dawley Rats Structure System Testing Therapeutic Time Tissues Transcript Translations Up-Regulation Western Blotting Work base constriction heart function heart metabolism in vivo inorganic phosphate novel novel therapeutics nucleotide metabolism preservation pressure prevent rat genome response transcriptome sequencing ward

项目摘要

Project Summary Currently, 6.5 million Americans are diagnosed with heart failure, a cardiovascular disease that is classically defined as the impaired ability of the heart to pump oxygenated and nutrient full blood to meet the demands of the body. The mechanical function of the heart is driven by the chemical free energy provided by ATP hydrolysis. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the chemical potential that is available to drive cellular processes. The concentrations of creatine (Cr), phosphocreatine (CrP), and ATP and the CrP/ATP ratio are diminished in heart failure, while levels of inorganic phosphate are increased. These changes in energy metabolite levels have been shown to be driven, at least in part, by reductions in total adenine nucleotide (TAN) pool levels. In vivo the TAN pools are maintained via a balance between the purine de novo synthesis and degradation pathways. In disease there is an increase in mammalian target of rapamycin complex 1 (mTORC1) phosphorylation, which causes an upregulation of the purine de novo synthesis pathway. In addition, it has been observed that levels of enzymes involved in the purine degradation pathway are decreased during failure. Furthermore, reductions in TAN should kinetically activate the purine synthesis pathway. Together, these compensations are not enough to maintain physiological TAN pool levels in heart failure. The goals of this proposal are to elucidate the underlying mechanism driving the depletion of the TAN pools in heart failure and to explore possible therapeutics to reverse this pathological metabolite depletion in patients with heart failure. The hypothesis of this study is that in a high demand state associated with the pressure- and volume-overloaded heart, the metabolic state of the myocardium is shifted towards purine degradation. This shift is only partially compensated for by changes in expression level of enzymes in the synthesis and degradation pathways. In three aims, we will assay and modulate expression of key genes in the purine degradation, salvation, and de novo synthesis pathways that are differentially regulated in heart failure, to test our hypothesis, and to identify and test novel molecular targets to reverse myocardial energetic dysfunction.

项目摘要目前，有650万美国人被诊断出患有心力衰竭，这是一种经典的心血管疾病定义为心脏泵送氧合和营养全血的能力受损，以满足的需求身体。心脏的机械功能由ATP提供的化学自由能驱动水解。心肌消耗的生理速率要求心脏重新合成其整个ATP 每分钟池几次。在失败的心脏中，心肌细胞代谢功能障碍导致降低可用于驱动细胞过程的化学潜力。肌酸（CR）的浓度，心力衰竭的磷酸盐（CRP），ATP和CRP/ATP比率降低，而无机水平磷酸盐增加。这些能量代谢物水平的变化已被证明是驱动的，至少在部分，通过降低总腺嘌呤核苷酸（TAN）池水平。在体内，棕褐色的池是通过在从头合成与降解途径之间的平衡。在疾病中有所增加雷帕霉素络合物1（MTORC1）磷酸化的哺乳动物靶标，导致上调嘌呤从头综合途径。另外，已经观察到参与嘌呤降解途径在失败期间降低。此外，棕褐色的减少应在动力学上激活嘌呤合成途径。在一起，这些补偿不足以维持心力衰竭的生理棕褐色池水平。该提案的目标是阐明驱动棕褐色耗竭的基本机制心力衰竭的池并探索可能逆转这种病理代谢物耗竭的可能治疗剂心力衰竭的患者。这项研究的假设是，在高需求状态下压力和体积遍布的心脏，心肌的代谢状态转向嘌呤降解。这种转移仅通过在表达水平的变化中部分补偿。合成和降解途径。在三个目标中，我们将测定并调节关键基因在嘌呤降解，救恩和从头衰竭差异调节的从头综合途径，测试我们的假设，并识别和测试新的分子靶标，以逆转心肌能量功能障碍。