AMP-activated protein kinase in the ischemic heart

缺血心脏中的 AMP 激活蛋白激酶

基本信息

批准号：
8288246
负责人：
LAWRENCE H YOUNG
金额：
$ 40.96万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288246
关键词：
5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Address Apoptosis Area Arteries Award Biogenesis Biological Biology Blood flow Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Cardiac Cardiac Myocytes Cells Clinical Collaborations Complex Coronary Arteriosclerosis Data Development Diabetes Mellitus Disease Effectiveness Foundations Funding Genetic Models Genetic Polymorphism Genetic Transcription Goals Health Heart Human Hypoxia Immigration Inflammatory Injury Ischemia Ischemic Preconditioning Knockout Mice Laboratories Lead Malignant Neoplasms Mediating Metabolic Metabolic Pathway Migration Inhibitory Factor Mitochondria Molecular Molecular Genetics Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Necrosis Organ Oxygen Pathway interactions Patients Phosphotransferases Physiological Process Protein Kinase Reagent Regulation Reperfusion Therapy Research Research Personnel Role SLC2A1 gene STK11 gene Signal Pathway Signal Transduction Stress Technical Expertise Testing Therapeutic Transgenic Mice Tumor Suppressor Proteins Work autocrine base body system cytokine glucose transport heart metabolism human disease innovation insight novel novel strategies novel therapeutic intervention paracrine phenylpyruvate tautomerase preconditioning prevent promoter receptor research study response therapeutic target treatment strategy tumor upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The overall aim of our research is to define the cellular and molecular mechanisms determining the response of the heart to myocardial ischemia, with the long-term goal to develop novel therapeutic approaches for patients with coronary artery disease. The AMP-activated protein kinase (AMPK) is emerging as an important intracellular signaling pathway with important relevance to human disease, including ischemic heart disease, diabetes, and cancer. AMPK modulates major metabolic pathways, gene transcription, and mitochondrial biogenesis. Our laboratory has elucidated the importance of AMPK in the heart, where it protects against myocardial injury during ischemia and reperfusion. Impaired AMPK activation in the heart compromises ischemic glucose transport, impairs post-ischemic contractile function and exacerbates necrosis and apoptosis during ischemia-reperfusion. We have also recently introduced a novel paradigm for AMPK activation, based on our discovery that the cytokine macrophage migration inhibitory factor (MIF) has an autocrine/paracrine effect to amplify AMPK activation during ischemia. Isolated hearts from MIF knockout mice have impaired AMPK activation and poor ischemic tolerance, suggesting that MIF has a physiological role in the response to ischemia. These results have potential clinical importance, since we also found that a common polymorphism in the MIF promoter leads to impaired MIF secretion and AMPK activation during hypoxia in human cells. The proposed experiments will build on our prior research and address key new questions that will elucidate the regulation of the AMPK pathway and its potential for therapeutic application. We will 1) determine the molecular signal transduction mechanisms through which MIF activates AMPK and the specific role of cardiomyocte-derived MIF during ischemia, 2) define the roles of the tumor suppressing kinase LKB1 and calcium calmodulin-activated protein kinase kinase (CaMKK2) in AMPK activation in the ischemic heart and 3) develop therapeutic approaches with novel AMPK activators to protect the heart against ischemic injury. The experiments outlined in the current proposal utilize innovative cellular, molecular, genetic and physiologic approaches that we have developed during the prior funding period. They draw on the investigators' combined expertise in the areas of cellular cardiac metabolism, ischemic heart disease, MIF biology and inflammatory disease. Through the combined use of pharmacologic reagents and genetic models, the proposed experiments will determine whether activation of AMPK is an effective strategy to protect the heart against ischemic injury. Thus, the proposed research aims to define novel biological aspects of ischemic heart disease and incorporates translational strategies that have promise to lead to novel treatment strategies for patients with coronary artery disease. PUBLIC HEALTH RELEVANCE: People with hardening of the arteries or coronary artery disease can develop heart attacks from a lack of blood flow and oxygen delivery to their heart muscle. The purpose of this research is to identify key molecules in the heart that can prevent damage during a heart attack. We propose to develop novel strategies, directed at these molecules, that may lead to the development of new treatments for patients with coronary artery disease.

描述（由申请人提供）：我们研究的总体目的是定义确定心脏对心肌缺血的反应的细胞和分子机制，其长期目标是为冠状动脉疾病患者开发新的治疗方法。 AMP激活的蛋白激酶（AMPK）正在成为重要的细胞内信号通路，与人类疾病（包括缺血性心脏病，糖尿病和癌症）重要相关。 AMPK调节主要的代谢途径，基因转录和线粒体生物发生。我们的实验室已经阐明了AMPK在心脏中的重要性，在缺血和再灌注期间，它可以防止心肌损伤。心脏中AMPK激活受损会损害缺血性葡萄糖的转运，损害缺血后的收缩功能，并加剧缺血性灌注过程中坏死和凋亡。我们最近还引入了一种新型的AMPK激活范式，这是基于我们的发现，即细胞因子巨噬细胞迁移抑制因子（MIF）具有自分泌/旁分泌效应，以扩大缺血期间的AMPK激活。来自MIF敲除小鼠的分离心脏损害了AMPK激活和缺血性耐受性差，这表明MIF在对缺血的反应中具有生理作用。这些结果具有潜在的临床重要性，因为我们还发现MIF启动子中常见的多态性会导致人类细胞中缺氧期间MIF分泌和AMPK激活受损。拟议的实验将基于我们先前的研究，并解决将阐明AMPK途径的调节及其治疗应用潜力的关键新问题。我们将1）确定MIF激活AMPK的分子信号转导机制，以及局部缺血期间心肌衍生的MIF的具体作用，2）定义肿瘤抑制激酶LKB1和钙钙调硫素激活蛋白激活蛋白激活的蛋白激酶激酶（Camkkk2）在AMPK 2中的作用，在AMPK 2中的新颖性作用。 AMPK激活剂可保护心脏免受缺血性损伤。当前提案中概述的实验利用了我们在上一家资金期间开发的创新细胞，分子，遗传和生理方法。他们借鉴了研究人员在细胞心脏代谢，缺血性心脏病，MIF生物学和炎症性疾病领域的综合专业知识。通过联合使用药理学试剂和遗传模型，提出的实验将确定AMPK的激活是否是保护心脏免受缺血性损伤的有效策略。因此，拟议的研究旨在定义缺血性心脏病的新生物学方面，并结合了有望为冠状动脉疾病患者提供新的治疗策略的翻译策略。公共卫生相关性：动脉或冠状动脉疾病硬化的人会因缺乏血液流动和氧气输送到心脏肌肉而产生心脏病发作。这项研究的目的是确定心脏中可以防止心脏病发作损害的关键分子。我们建议开发针对这些分子的新型策略，这可能会导致针对冠状动脉疾病患者开发新的治疗方法。