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：
10364407
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/10364407
关键词：
Acute Affect Anabolism Antineoplastic Agents Arteries Aspartate Biological Assay Carbamyl Phosphate Cardiac Cardiac Myocytes Cardiomyopathies Cell Death Cessation of life Clinical Coronary Coronary artery Coupling Data Development Dihydroorotase Disease Drug Targeting Electrophysiology (science)Enzymes Epidemic Functional disorder Future Genetically Engineered Mouse Goals Growth Healthcare Heart Heart Arrest Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Hypertension In Vitro Infarction Injury Ischemia Knock-out Knowledge Ligase Light 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 base blood pressure elevation cardioprotection caspase-activated deoxyribonuclease clinical practice coronary artery occlusion design enzyme pathway experimental study 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.

项目概要高血压和缺血性心脏病是心力衰竭的两个最重要的危险因素。在对血压升高的反应，心脏表现出肥厚生长以改善心室壁压力。这种曾经的适应性反应可能会失代偿并进展为心力衰竭。另一方面，心肌梗塞会导致心脏的严重结构损伤。临床常见治疗方法通过冠状动脉恢复引起的心脏缺血会导致额外的再灌注损伤。缺血带来的侮辱和再灌注一起显着削弱心脏的泵血功能。尽管有广泛的兴趣和由于临床需求迫切，我们对心力衰竭发展机制的了解仍然有限。病理性心脏重塑是高血压和缺血性心脏病的常见途径。在对需求增加或心脏损伤的反应，心脏会做出急性反应来补偿心肌收缩力丧失。然而，在持续的压力下，会发生失代偿和心力衰竭发展。先前的研究表明，代谢改变先于大多数（如果不是全部）其他变化。病理性心脏重塑。然而，心脏代谢重塑的贡献和机制失败仍然难以捉摸。初步结果表明，嘧啶从头生物合成急剧且显着增强心脏对压力超负荷、结构和电生理变化的反应。而且， Cad（氨基甲酰磷酸合成酶 2、天冬氨酸转氨甲酰酶和二氢乳清酶）作为限速该途径的酶被强烈诱导。另一方面，嘧啶的从头生物合成也是缺血后再灌注上调。根据之前的发现和这些试点数据，假设病理性心脏重塑中的嘧啶生物合成已被制定。既有增益也有损失功能小鼠模型已生成，将用于测试 1) Cad 和 de novo 的作用嘧啶生物合成在压力超负荷诱发的心肌病中的作用，2) Cad 和从头嘧啶的作用心脏缺血/再灌注引起的病理性心脏重塑，以及 3) 使用 Cad 的可行性在高血压和缺血性心脏病条件下阻止心力衰竭发展的抑制剂。体外将使用原代心肌细胞培养物进行实验以证实体内测试。说明从头嘧啶生物合成在病理性心脏重塑和心力衰竭中的作用将增进我们对高血压和缺血性心脏病病理生理学的理解并铺平道路新颖、更有效的治疗设计。