Period in Cardio Protection

心脏保护期

• 批准号: 8461977
• 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
• 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/8461977
• 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; public health relevance; response; skills

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）：这个为期5年的培训计划提出了作为心肌缺血和心脏生物学领域的独立生物医学研究人员的职业发展计划。主要研究者是一名委员会认证的麻醉师，并已完成重症监护奖学金培训。与赞助商和经验丰富的合作者，他将扩大他的科学技能，为职业发展作为一个独立的医生，科学家做准备。该计划将强调在心肌细胞功能和缺血-适应性过程的调节在体外（分离的心肌细胞暴露于缺氧）和体内（小鼠原位心肌缺血）模型的细胞内途径的分子生物学技能。为了提高他在代谢生物学方面的知识，他将参加丹佛国立犹太大学组学技术项目提供的课程。部门负责人托马斯亨索恩（医学博士）将提供赞助。Holger Eltzschig医学博士，国际器官缺氧和缺血分子生物学专家将担任专门的导师并提供赞助。该计划将受益于Sean Colgan博士的合作专业知识，Sean Colgan博士是导致适应缺氧的分子机制的世界专家，他将为细胞内途径，翻译后机制和代谢研究的研究提供咨询支持。此外，世界著名的心脏病专家Peter Buttrick医学博士和Michael布里斯托医学博士将每16周与Eltzschig和Colgan博士合作并在一个咨询委员会中任职。该委员会将审查进展情况，并提供密切的科学支持和职业建议。 心肌缺血（MI）是一种永久性的严重医学问题。在过去的几十年中，令人信服的证据已经证明腺苷生成在心脏缺血预处理（IP）中的信号传导中的核心作用，该现象被称为针对心肌缺血的最强体内形式的保护。因此，许多可能的效应物已被确定为对介导心脏IP至关重要。然而，IP启动的途径完全未知。在这项研究中，我们目前的数据从一个微阵列，我们确定了两个昼夜节律蛋白，周期1和周期2，作为腺苷依赖分子。在后者中，我们可以证实IP和腺苷依赖性诱导和稳定这两个节奏蛋白。在Per 2-/-小鼠中的以下研究揭示了Period在IP和心脏缺血中的功能作用。Per 2-/-小鼠有更大的梗死面积，并取消了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导作用，并且据报道控制线粒体代谢，因此我们接下来对线粒体中的主要耗氧酶ATP合酶进行研究。我们发现，这种酶下调，由于IP在野生型，但不是在周期缺陷小鼠。基于这些发现，我们假设周期介导代谢组织适应，这是心脏IP的核心。设计了三个具体目标，以解决MI时期的新角色。(1)在第一个目标中，我们建议通过结合药理学和遗传学方法来研究体外周期稳定的调节机制和后果。(2)在第二个目标中，我们将结合联合收割机在体外和体内的研究，以探讨代谢途径启动的周期稳定。在第三个目标中，通过利用组织特异性小鼠周期，我们将首先阐明内皮细胞和心肌细胞在体内对MI的单独贡献。最后，我们将心脏周期作为使用强光照射治疗MI的治疗选择。这些研究旨在阐明MI期间调节细胞损伤的内源性途径。靶向这些途径将为MI治疗中的新型和特异性治疗方法奠定基础，这是改善发病率和死亡率所迫切需要的。