Period in Cardio Protection

心脏保护期

基本信息

批准号：
8661030
负责人：
Tobias Eckle
金额：
$ 13.15万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-07 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661030
关键词：
Address Adenosine Adenosine A3 Receptor Advisory Committees Agonist Area Attenuated Biology Brain Hypoxia-Ischemia Cardiac Cardiac Myocytes Cells Circadian Rhythms Coronary artery Critical Care Cyclic AMP Data Degradation Pathway Developed Countries Development Plans Doctor of Philosophy Down-Regulation Endothelial Cells Endothelium Enzymes Exposure to Fellowship Gene Targeting Generations Genetic Glucose Grant Head Heart Hypoxia In Situ In Vitro Individual Infarction International Investigation Ischemia Ischemic Preconditioning Knockout Mice Knowledge Light Magnetic Resonance Imaging Mediating Medical Mentors Metabolic Metabolic Pathway Metabolism Microarray Analysis Mitochondria Mitochondrial Proton-Translocating ATPases Modeling Molecular Molecular Biology Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Nuclear Organ Oxygen Pathway interactions Patients Physicians Play Preparation Principal Investigator Process Proteins Purinergic P1 Receptors Regulation Relative (related person)Reperfusion Therapy Reporting Research Design Research Personnel Role Scientist Signal Pathway Signal Transduction System Technology Therapeutic Tissues Training Training Programs Transcript Weight artery occlusion attenuation base career cell injury defined contribution design expectation experience extracellular follower of religion Jewish improved in vitro Model in vivo inorganic phosphate metabolic abnormality assessment mortality myocardial hypoxia myocardial infarct sizing novel preconditioning programs response skills

项目摘要

DESCRIPTION (provided by applicant): This 5-year training program proposes the development plan for a career as an independent biomedical researcher in the area of myocardial ischemia and cardiac biology. The principal investigator, is a board certified Anesthesiologist and has completed a Critical Care Fellowship training. With the sponsors and experienced collaborators he will expand on his scientific skills in preparation for career progression as an independent physician-scientist. The program will emphasize skills in molecular biology of intracellular pathways in myocyte function and regulation of ischemia- adaptive processes using in vitro (isolated myocytes exposed to hypoxia) and in vivo (murine in situ myocardial ischemia) models. To advance his knowledge in metabolic biology he will attend courses offered by the Omics Technologies Program at the National Jewish, Denver. Thomas Henthorn, MD, the Departmental Head will provide sponsorship. Holger Eltzschig MD, PhD, an international expert in molecular biology of organ hypoxia and ischemia will be the dedicated mentor and provide sponsorship. The program will benefit from collaborative expertise of Sean Colgan PhD, a world expert in molecular mechanisms leading to adaptation to hypoxia, who will provide consultative support for the studies on intracellular pathways, posttranslational mechanisms and metabolic studies. Additionally, Peter Buttrick, MD and Michael Bristow MD, PhD, both world renowned cardiologists, will collaborate and serve with Drs. Eltzschig and Colgan on an advisory committee every 16 weeks. This committee will review progress and provide close scientific support and career advice. Myocardial ischemia (MI) is a permanent and serious medical problem. Over the last decades, convincing evidence has demonstrated a central role of adenosine generation in signaling in cardiac ischemic preconditioning (IP), a phenomenon known as the strongest in vivo-form of protection against myocardial ischemia. As such, many possible effectors have been identified to be critical for mediating IP of the heart. However, the pathway initiated by IP is completely unknown. In this study, we present data from a microarray where we identified two circadian rhythm proteins, Period 1 and Period 2, as adenosine dependant molecules. In the latter we could confirm an IP and adenosine dependant induction and stabilization of these two rhythm proteins. Following studies in Per2-/- mice revealed a functional role of Period in IP and ischemia of the heart. Per2-/- mice had bigger infarct sizes and abolished cardioprotection mediated by IP. Since circadian rhythm proteins are known to play a dominant role in metabolic processes and are reported to control mitochondrial metabolism, we next pursued studies on the main oxygen consuming enzyme in mitochondria, the ATP Synthase. We found that this enzyme was downregulated due to IP in wildtype, but not in Period deficient mice. Based on these findings we hypothesize that Periods mediate metabolic tissue adaptation which is central to cardiac IP. Three specific aims were designed to address novel roles for Period in MI. (1) In the first aim, we propose to study regulatory mechanisms and consequences of Period stabilization in vitro by combining pharmacological and genetic approaches. (2) In the second aim, we will combine in vitro and in vivo studies to investigate metabolic pathways initiated by period stabilization. In the third aim, by utilizing tissue specific mice for Period, we will first elucidate the individual contribution of endothelium and cardiomyocytes to MI in vivo. Finally, we will target Period in the heart as therapeutic option to treat MI using intense light exposure. These studies are designed to shed new light on endogenous pathways that regulate cell injury during MI. Targeting such pathways will lay the groundwork for novel and specific therapeutic approaches in the treatment of MI, which are urgently needed to improve morbidity and mortality.

描述（由申请人提供）：这项为期5年的培训计划提出了在心肌缺血和心脏生物学领域的独立生物医学研究人员职业的发展计划。首席研究员是一名经过认证的麻醉师，并完成了重症监护奖学金培训。在赞助商和经验丰富的合作者中，他将扩大自己的科学技能，为作为独立医师科学家的职业发展做准备。该计划将强调使用体外（暴露于缺氧的孤立的心肌细胞）和体内（鼠（Murine into int ot）（鼠类原位心肌缺血）模型，使用体外（孤立的心肌细胞）模型的细胞内途径的分子生物学技能。为了促进他在代谢生物学方面的知识，他将参加丹佛国家犹太人的Omics Technologies计划提供的课程。部门负责人托马斯·亨索恩（Thomas Henthorn）将提供赞助。 Holger Eltzschig MD博士是器官缺氧和缺血分子生物学的国际专家，将成为专门的导师，并提供赞助。该计划将受益于肖恩·科尔根（Sean Colgan Phd）的合作专业知识，后者是分子机制的全球专家，导致对缺氧的适应性，他们将为细胞内途径，翻译后机制和代谢研究的研究提供咨询支持。此外，医学博士彼得·巴特里克（Peter Buttrick）和迈克尔·布里斯托（Michael Bristow）博士，都是世界著名的心脏病专家，将与博士合作并服务。 Eltzschig和Colgan在咨询委员会举行一次。该委员会将审查进度，并提供密切的科学支持和职业建议。心肌缺血（MI）是一个永久而严重的医疗问题。在过去的几十年中，令人信服的证据表明，腺苷产生在心脏缺血预处理（IP）中的核心作用，这是一种被称为最强的对心肌缺血的保护形式最强的现象。因此，已经确定许多可能的效应子对于介导心脏IP至关重要。但是，IP启动的途径是完全未知的。在这项研究中，我们从微阵列中介绍了数据，其中我们将两个昼夜节律蛋白（周期1和周期2）确定为腺苷依赖性分子。在后者中，我们可以确认这两种节奏蛋白的IP和腺苷依赖性诱导和稳定。经过PER2 - / - 小鼠的研究表明，周期在IP和心脏缺血中的功能作用。 PER2 - / - 小鼠具有较大的梗塞大小，并废除了由IP介导的心脏保护。由于已知昼夜节律蛋白在代谢过程中起主要作用，并据报道可以控制线粒体代谢，因此我们接下来对ATP合酶线粒体中主要氧气消耗酶进行研究。我们发现，由于野生型中的IP，这种酶被下调，但在周期不足的小鼠中没有下调。根据这些发现，我们假设时期介导了心脏IP核心的代谢组织适应。设计了三个特定的目标，以解决MI中时期的新作用。（1）在第一个目标中，我们建议通过结合药理和遗传方法来研究体外时期稳定的调节机制和后果。（2）在第二个目标中，我们将结合体外研究和体内研究，以研究通过周期稳定引发的代谢途径。在第三个目标中，通过利用组织特定的小鼠，我们将首先阐明内皮和心肌细胞对体内MI的个体贡献。最后，我们将以强烈的光线暴露为治疗MI的治疗选择。这些研究旨在为调节MI期间细胞损伤的内源性途径提供新的启示。靶向这种途径将为MI治疗中的新颖和特定的治疗方法奠定基础，MI的治疗迫切需要改善发病率和死亡率。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial: Health Impact and Management of a Disrupted Circadian Rhythm and Sleep in Critical Illnesses.

DOI：
10.2174/1381612821999150709123504
发表时间：
2015
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
Eckle T
通讯作者：
Eckle T

Cardiac period 2 in myocardial ischemia: clinical implications of a light dependent protein.

DOI：
10.1016/j.biocel.2012.12.022
发表时间：
2013-03
期刊：
The international journal of biochemistry & cell biology
影响因子：
0
作者：
Bonney S;Hughes K;Harter PN;Mittelbronn M;Walker L;Eckle T
通讯作者：
Eckle T

Analysis of selected sugars and sugar phosphates in mouse heart tissue by reductive amination and liquid chromatography-electrospray ionization mass spectrometry.

DOI：
10.1021/ac400769g
发表时间：
2013-06-18
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
Han, Jun;Tschernutter, Vera;Yang, Juncong;Eckle, Tobias;Borchers, Christoph H.
通讯作者：
Borchers, Christoph H.

Cardiac Per2 functions as novel link between fatty acid metabolism and myocardial inflammation during ischemia and reperfusion injury of the heart.