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

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

展开

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.

项目摘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，心脏表现出肥厚性生长至改善心室壁压力。曾经的自适应反应可能会使心力衰竭失去并发展。另一方面，心肌梗塞会引起心脏的重大结构损害。治疗的常见临床实践通过恢复冠状动脉的心脏缺血导致额外的再灌注损伤。缺血的侮辱再灌注会显着削弱心脏的抽水功能。尽管有广泛的兴趣和紧急临床需求，我们对心力衰竭发育机制的理解仍然有限。病理心脏重塑是高血压和缺血性心脏病的常见途径。在对需求升高或心脏损伤的反应，心脏会施加急性反应以补偿心脏收缩的损失。然而，在持续的压力下，发生了代偿性和心力衰竭发展。先前的研究表明，代谢的改变是大多数（如果不是全部）的大部分变化病理心脏重塑。但是，代谢重塑的贡献和机制失败仍然难以捉摸。这里的初步结果表明，从头嘧啶的生物合成急剧而显着增强在响应压力超负荷的心脏中，结构和电生理改变。而且， CAD（氨基甲酸酯合成酶2，天冬氨酸经氨基甲基酶和二氢酶）作为速率限制该途径的酶强烈诱导。另一方面，从头嘧啶的生物合成也是缺血后被再灌注上调。根据以前的发现和这些试验数据，一个假设病理心脏重塑中的嘧啶生物合成已被制定。收获和丧失已经生成了将用于测试的功能鼠标模型1）CAD和DE NOKO的作用压力超负荷引起的心肌病中的嘧啶生物合成，2）CAD和DE NOKO嘧啶的作用在心脏缺血/再灌注引起的病理心脏重塑中，以及3）使用CAD的可行性在高血压和缺血性心脏病状况下阻止心力衰竭发育的抑制剂。体外使用原发性心肌细胞培养的实验将进行证实体内测试。阐明从病态心脏重塑和心力衰竭中新生嘧啶生物合成的作用促进我们对高血压和缺血性心脏病的病理生理学的理解，并以一种方式铺平用于新颖，更有效的治疗设计。