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

• 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
• 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' -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

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，650万美国人被诊断患有心力衰竭，这是一种典型的心血管疾病， 定义为心脏泵送含氧和营养的全血以满足 身体心脏的机械功能是由ATP提供的化学自由能驱动的 水解心肌ATP消耗的生理速率要求心脏重新合成其全部ATP 每分钟游泳几次。在衰竭的心脏中，心肌细胞代谢功能障碍导致 驱动细胞过程的化学势。肌酸（Cr）浓度， 磷酸肌酸（CrP）和ATP以及CrP/ATP比值在心力衰竭中减少，而无机肌酸（CrP）水平 磷酸盐增加。能量代谢物水平的这些变化已被证明是由驱动的，至少在 部分是通过减少总腺嘌呤核苷酸（TAN）库水平。在体内，TAN池通过 嘌呤从头合成和降解途径之间的平衡。在疾病中， 雷帕霉素复合物1（mTORC 1）的哺乳动物靶磷酸化，这导致上调的雷帕霉素复合物1（mTORC 1）的磷酸化， 嘌呤从头合成途径。此外，已经观察到，参与代谢的酶的水平在一定程度上是不稳定的。 嘌呤降解途径减少。此外，TAN的减少应在动力学上 激活嘌呤合成途径。这些补偿加在一起不足以维持 心力衰竭中的生理TAN池水平。 该提案的目标是阐明驱动TAN耗尽的潜在机制 并探索可能的治疗方法来逆转这种病理性代谢物消耗， 心力衰竭患者。这项研究的假设是，在高需求状态下， 压力和容量超负荷的心脏，心肌的代谢状态向嘌呤转移 降解这种转变仅部分地被细胞中酶表达水平的变化所补偿 合成和降解途径。在三个目标中，我们将检测和调节在细胞中的关键基因的表达， 在心力衰竭中差异调节的嘌呤降解、拯救和从头合成途径， 为了验证我们的假设，并确定和测试新的分子靶点，以逆转心肌能量 功能障碍