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Role of de novo pyrimidine biosynthesis in pathological cardiac remodeling

从头嘧啶生物合成在病理性心脏重塑中的作用

基本信息

批准号：
10579222
负责人：
Zhao Wang
金额：
$ 44万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579222
关键词：
Acute Affect Anabolism Antineoplastic Agents Arteries Aspartate Biological Assay Carbamyl Phosphate Cardiac Cardiac Myocytes Cardiomyopathies Cell Death Cessation of life Clinical Compensation Coronary Coronary artery Coupling Data Development Dihydroorotase Disease Drug Targeting Electrophysiology (science)Enzymes Epidemic Functional disorder Future Genetically Engineered Mouse Goals Growth Healthcare Systems Heart Heart Arrest Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Hypertension In Vitro Infarction Injury Ischemia Knock-out Knowledge Legal patent Ligase Metabolic Metabolic Pathway Molecular Molecular Analysis Muscle Cells Myocardial Infarction Myocardial Ischemia N phosphonoacetyl L aspartate Pathologic Pathway interactions Persons Pharmaceutical Preparations Phenotype Physiological Post-Translational Protein Processing Production Public Health Pump Pyrimidine Rattus Reaction Recovery Reperfusion Injury Reperfusion Therapy Risk Factors Role Route Signal Pathway Stress Testing Therapeutic Vascular blood supply Ventricular blood pressure elevation cardioprotection clinical practice coronary artery occlusion design enzyme pathway experimental study gain of function heart damage heart function hypertensive in vivo in vivo evaluation inhibitor insight interest ischemic injury loss of function metabolomics mortality mouse model myocardial damage novel novel therapeutic intervention overexpression pilot test pressure response restoration therapeutically effective transcarbamylase

项目摘要

Project Summary Hypertensive and ischemic heart diseases are the two most important risk factors of heart failure. In response to elevated blood pressure, the heart manifests hypertrophic growth to ameliorate ventricular wall stress. This once adaptive response may decompensate and progress into heart failure. On the other hand, myocardial infarction causes significant structural damage of the heart. The common clinical practice to treat cardiac ischemia via restoration of coronary arteries leads to additional reperfusion injury. Insults from ischemia and reperfusion together significantly weaken the pumping function of the heart. Despite extensive interests and urgent clinical needs, our understanding of the mechanisms for heart failure development remains limited. Pathological cardiac remodeling is a common route of both hypertensive and ischemic heart diseases. In response to either elevated demand or cardiac damage, the heart mounts an acute reaction to compensate for the loss of cardiac contractility. Under persistent stress, however, decompensation occurs and heart failure develops. Previous studies have shown that metabolic alteration precedes most if not all other changes during pathological cardiac remodeling. However, the contribution and mechanism of metabolic remodeling in heart failure is still elusive. Preliminary results here show that de novo pyrimidine biosynthesis is acutely and significantly augmented in the heart in response to pressure overload, preceding structural and electrophysiological alterations. Moreover, Cad (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as the rate-limiting enzyme of this pathway is strongly induced. On the other hand, de novo pyrimidine biosynthesis is also upregulated by reperfusion after ischemia. Based on previous findings and these pilot data, a hypothesis of pyrimidine biosynthesis in pathological cardiac remodeling has been formulated. Both gain-of and loss-of- function mouse models have been generated that will be employed to test 1) the role of Cad and de novo pyrimidine biosynthesis in pressure overload-induced cardiomyopathy, 2) the role of Cad and de novo pyrimidine in cardiac ischemia/reperfusion-caused pathological cardiac remodeling, and 3) the feasibility of using a Cad inhibitor to arrest heart failure development under hypertensive and ischemic heart disease conditions. In vitro experiments using primary cardiac myocyte culture will be performed to corroborate the in vivo tests. Elucidation of the role of de novo pyrimidine biosynthesis during pathological cardiac remodeling and heart failure will advance our understanding of the pathophysiology of hypertensive and ischemic heart diseases and pave a way for novel, more effective therapeutic design.

项目总结