Mechanisms of myocardial ischemia and reperfusion

心肌缺血和再灌注的机制

基本信息

批准号：
8774406
负责人：
Dorothy Eileen Vatner
金额：
$ 7.95万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8774406
关键词：
Acute Adrenergic Receptor Animal Model Animals Apoptosis Basic Science Binding Biochemical Cardiac Cardiovascular system Cell Death Cell Survival Cells Characteristics Chronic Clinical Clinical Medicine Conscious Coronary Coronary Arteriosclerosis Coronary artery Country Denervation Exhibits Family suidae Fostering Functional disorder Funding Genetic Engineering Genomics Glues Health Heart Heart Diseases Heart failure Individual Ischemia Ischemic Preconditioning Left Ventricular Dysfunction Link Modeling Molecular Molecular Biology Molecular Genetics Morbidity - disease rate Myocardial Myocardial Hibernation Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Myocardial Stunning Myocardium Necrosis Oxygen Pathogenesis Pathologist Pathology Patients Phosphotransferases Physiological Physiology Prevalence Protein Kinase Proteomics Recovery Research Research Personnel Rodent Rodent Model Role Science Scientist Sterility Stress Stunned Myocardium Sudden Death Sum Techniques Therapeutic Intervention Vascular blood supply Work artery occlusion base design experience improved in vivo Model instrument mortality novel programs response tool

项目摘要

DESCRIPTION (provided by applicant): The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of this Program Project application is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing a combined approach by integrative and basic scientists. There are 4 projects and 5 cores, with major interactions among projects and cores. All the projects include cellular and molecular studies as well as integrative whole animal physiology. All Projects use all the Cores, which is the glue that binds the Projects and provides the synergy characteristic of a Program Project. One unique aspect of this Program Project is the use of the large mammalian model, which is central to Projects 1 and 2. Project 1, "Effects of Cardiac Denervation on Ischemic Protection", involves the study of the mechanisms of cardiac protection in the second window of ischemic protection in chronically instrumented conscious swine. The project is based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor blockade abrogates the second window of protection. Project 2, "Molecular Mechanisms in Chronically Stunned Myocardium", parallels Project 1 in that it also uses the conscious, chronically instrumented swine model, but focuses on the chronic, repetitive stunning model developed in this project in the last funding period. This model recapitulates many of the features of hibernating myocardium in patients with chronic coronary artery disease, and also exhibits myocardial protection, potentially through a third window of protection. Project 3, "Cell Death Promoting Mechanisms of Mst 1", also involves the study of cell survival and cell death with special emphasis on the molecule Mst 1, mammalian sterile kinase. This project is based on findings during the current funding period that Mst 1, belonging to a recently identified evolutionary conserved protein kinase cascade activated by myocardial ischemia, has unexpected and diverse functions not limited to pro-apoptosis but which contributes to cardiac dysfunction. Project 4, "Survival Role of H11 Kinase during Myocardial Ischemia", is a new project which focuses on cardioprotection mechanisms invoked by H11 kinase. This project is based on work completed during the initial funding period, where one of the novel molecular mechanisms involved in myocardial stunning and hibernation discovered was H11 kinase, a molecule not previously studied in the heart, and found to afford powerful protection against myocardial ischemia. The Program Project approach is exemplified by the interactions among Projects and Cores, which strengthens each individual project and is designed to improve our understanding and delineate new therapies for patients with coronary artery disease.

描述（由申请人提供）：心脏病的最常见形式是心肌缺血，其特征是由于冠状动脉阻塞引起的血液，底物和氧气供应不足。如果未接受治疗，则以心肌梗塞形式（心脏病发作）的形式发生不可逆的损害。该计划项目应用的总体目的是确定对理解缺血性心脏病至关重要的机制，这将通过利用综合和基础科学家的合并方法来实现。有4个项目和5个核心，在项目和核心之间进行了主要互动。所有项目包括细胞和分子研究以及整个动物生理。所有项目都使用所有核心，即粘合项目并提供程序项目的协同特征的胶水。该计划项目的一个独特方面是使用大型哺乳动物模型，该模型对项目1和2。项目1的核心，“心脏神经对缺血性保护的影响”，涉及在长期仪器有意识的猪中对缺血性保护的第二个窗口中心脏保护机制的研究。该项目部分基于新颖的观察结果，即区域心脏神经或肾上腺素能受体阻滞消除了第二个保护窗口。项目2，“长期震惊的心肌的分子机制”，Parallels Project 1，因为它还使用了有意识的，长期仪器的猪模型，但专注于在最后一个资助期间在该项目中开发的慢性，重复性的惊人模型。该模型概括了慢性冠状动脉疾病患者冬眠心肌的许多特征，并且还可以通过第三个保护窗口表现出心肌保护。项目3，“促进MST 1的细胞死亡机制”，还涉及对细胞存活和细胞死亡的研究，并特别强调分子MST 1，哺乳动物无菌激酶。该项目基于当前资金期间的发现，即MST 1属于最近确定的进化保守的蛋白激酶级联反应，由心肌缺血激活，具有意外且多样化的功能，不仅限于促凋亡，但会导致心脏功能障碍。项目4，“ H11激酶在心肌缺血期间的生存作用”，是一个新项目，重点介绍了H11激酶调用的心脏保护机制。该项目基于在最初的资金期间完成的工作，其中一种新型的分子机制与心肌惊人和发现的冬眠相关的一种新型分子机制是H11激酶，这是一种先前未在心脏中研究的分子，发现对心肌缺血的强大保护具有强大的保护。项目和核心之间的相互作用来说明了计划项目方法，从而增强了每个项目，旨在提高我们的理解并为冠状动脉疾病患者描述新疗法。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging.

DOI：
10.1161/hypertensionaha.114.04456
发表时间：
2015-02
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
0
作者：
Sehgel NL;Sun Z;Hong Z;Hunter WC;Hill MA;Vatner DE;Vatner SF;Meininger GA
通讯作者：
Meininger GA

Why So Few New Cardiovascular Drugs Translate to the Clinics.

为什么很少有新的心血管药物转化为临床。

DOI：
10.1161/circresaha.116.309512
发表时间：
2016
期刊：
Circulation research
影响因子：
20.1
作者：
Vatner,StephenF
通讯作者：
Vatner,StephenF

Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes.

DOI：
10.1161/circresaha.108.193102
发表时间：
2009-04-10
期刊：
Circulation research
影响因子：
20.1
作者：
Rane S;He M;Sayed D;Vashistha H;Malhotra A;Sadoshima J;Vatner DE;Vatner SF;Abdellatif M
通讯作者：
Abdellatif M

Channel phosphorylation and modulation of L-type Ca2+ currents by cytosolic Mg2+ concentration.

通道磷酸化和胞质 Mg2 浓度对 L 型 Ca2 电流的调节。