Translational Center for In Vivo Mitochondrial Medicine

体内线粒体医学转化中心

• 批准号: 7852602
• 负责人: KEVIN E CONLEY
• 金额: $ 80.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852602
• 关键词: Acidosis; Age; Aging; Biological Models; Blood; Blood Vessels; Cell Death; Cell Energetics; Cell Survival; Cells; Clinical; Collaborations; Communities; Country; Coupling; Degenerative Disorder; Development; Diabetes Mellitus; Diagnostic; Diagnostic Procedure; Disease; Disease model; Economics; Engineering; Ensure; Equipment; Explosion; Failure; Functional disorder; Funding; Gap Junctions; Genetic; Genetic Models; Glycolysis; Goals; Health; Heart Diseases; Human; Human Resources; Huntington Disease; Intervention; Knowledge; Link; Magnetic Resonance; Malignant Neoplasms; Measurement; Measures; Medicine; Methodology; Methods; Mitochondria; Modeling; Monitor; Mus; Muscle; Muscle Cells; Nature; Nerve Degeneration; Optics; Oxidative Phosphorylation; Oxidative Stress; Parkinson Disease; Pathology; Phosphorylation; Population; Positioning Attribute; Procedures; Process; Production; Property; Protocols documentation; PubMed; Research; Research Infrastructure; Resources; Role; Scientist; Site; Stimulus; Stress; Symptoms; System; Systems Analysis; Techniques; Time; Tissues; Training; Translating; Variant; Work; age related; analytical tool; base; clinical application; clinically relevant; disease diagnosis; human disease; human tissue; improved; in vivo; innovation; insight; mitochondrial dysfunction; muscle aging; normal aging; programs; public health relevance; research study; respiratory; response; success; tool; uptake

DESCRIPTION (provided by applicant): Here we propose a center for collaborative studies that exploits transformational in vivo diagnostic tools to reveal the roles of mitochondria and cell energetics in cell health and disease using mouse and human muscle model systems. Mitochondria are now widely recognized as a nexus between cell energetics, oxidative stress, and cell survival in age-related degenerative diseases, cancer, heart disease and diabetes. An explosion of genetic models of mitochondrial dysfunction and human disease models provides an extraordinary opportunity for innovative new tools to reveal mitochondria's role in specific disease pathologies, especially in human tissues. Transformational tools that provide a new window on the cell to fully exploit these model systems are the core of the proposed center. The proposed initiative will fill the void in non-invasive approaches to study mitochondria in vivo to reveal how they ensure cell health but fail in symptomatic disease. Innovative magnetic resonance (MRS) and optical spectroscopic (OS) approaches permit measuring - for the first time in vivo - three key classes of energetic properties impacted by pathology: mitochondrial coupling (ATP/O2 or P/O) and capacity (O2max), cell glycolysis and ATP level, and cellular and vascular oxygenation (PO2). The proposed Translational Center will provide these tools and innovative approach for collaborative studies; provide new infrastructure for high throughput analyses, and new technical developments for improved measurements. Aim #1 establishes the Translational Center. Three steps are involved: 1) new personnel are hired and trained in the innovative tools and approaches, 2) new infrastructure is established to permit collaborative studies both locally and nationally and 3) new procedures and protocols are established to standardize the approach between mouse and human models for translational comparisons. Aim #2 integrates the spectroscopic tools for high throughput studies. OS and MRS probes are engineered to permit parallel spectroscopic measurements for increased throughput and expanded application for both mouse and human studies. New optical technical developments will greatly increase sensitivity and expand the subject populations available for our studies. Aim #3 disseminates these in vivo diagnostic methods to other sites involved in aging research. We propose to extend our success in dissemination to establish our in vivo diagnostic approach at 3 new research sites with high field clinical magnets and ongoing studies of aging human muscle. This will expand opportunities for critical breakthroughs as diverse research groups apply our innovative methods to a wide array of new experimental programs. The clinical relevance of the proposed center is the development of an approach that will transform our understanding of the role of mitochondrial dysfunction in disease by providing 1) new tools for disease diagnosis, 2) new insights into disease mechanisms, and 3) a new capability for monitoring interventions to halt or reverse disease symptoms. It will also promote economic stimulus through the hiring and retention of 5 new long-term positions and the purchase of 3 major pieces of equipment. PUBLIC HEALTH RELEVANCE: This work is relevant to human health because mitochondrial dysfunction is involved in most degenerative diseases, including diabetes, Parkinson's disease, Huntington's disease, and normal aging. However, there is a gap in our understanding of the role of mitochondrial dysfunction in these diseases due to a gap in our tools study mitochondrial function in vivo. We propose to create a new Translational Center for In Vivo Mitochondrial Medicine to further develop and expand our unique tools for in vivo study of mitochondrial function and cell energetics. This new initiative will facilitate new insights into the conditions that determine whether energetic stress leads to cell adaptation, as in healthy tissue, or cell loss and degeneration, as in diseases states. The goal of this new center will be to make our in vivo approach accessible to the broader research community to accelerate critical breakthroughs and translate these breakthroughs into clinical applications. The requested funds will be used to hire and train at least five new long-term positions and expand the infrastructure to increase the throughput of our experiments and analyses.

描述（由申请人提供）：在这里，我们提出了一个合作研究中心，该中心利用体内诊断工具的转化型，以使用小鼠和人类肌肉模型系统来揭示线粒体和细胞能量在细胞健康和疾病中的作用。现在，线粒体被广泛认为是与年龄相关的退行性疾病，癌症，心脏病和糖尿病的细胞能量，氧化应激和细胞存活之间的联系。线粒体功能障碍和人类疾病模型的遗传模型的爆炸爆炸为创新的新工具提供了非凡的机会，以揭示线粒体在特定疾病病理中的作用，尤其是在人体组织中。在电池上提供新窗口以充分利用这些模型系统的转换工具是拟议中心的核心。拟议的倡议将以非侵入性研究线粒体在体内研究线粒体的方法中填补空隙，以揭示它们如何确保细胞健康但在症状性疾病中失败。创新的磁共振（MRS）和光谱（OS）方法允许测量 - 首次在体内 - 受病理影响影响的三个关键类别的能量特性：线粒体偶联（ATP/O2或P/P/O）和能力（O2max），（O2max），细胞糖溶解和细胞级别和细胞级和氧气级别，和氧气和氧气级别和氧气级别（Po2）。拟议的翻译中心将为协作研究提供这些工具和创新的方法；为高吞吐量分析提供新的基础架构，并为改进测量值提供新的技术发展。 AIM＃1建立了转化中心。涉及三个步骤：1）在创新工具和方法中雇用和培训新人员，2）建立了新的基础设施，以允许在本地和国家进行协作研究，以及3）建立了新的程序和协议，以标准化鼠标和人类模型之间的方法进行翻译比较。 AIM＃2集成了用于高通量研究的光谱工具。 OS和MRS探针经过设计，以允许平行光谱测量值，以增加小鼠和人类研究的吞吐量和扩大应用。新的光学技术发展将大大提高灵敏度，并扩大可用于我们研究的主题人群。目标＃3将这些体内诊断方法传播到涉及衰老研究的其他站点。我们建议在传播方面扩展我们的成功，以在3个新的研究地点建立我们的体内诊断方法，并具有高场临床磁铁和正在进行的人类肌肉的持续研究。随着各种研究小组将我们的创新方法应用于各种各样的新实验计划，这将扩大关键突破的机会。所提出的中心的临床相关性是开发一种方法，该方法将通过提供1）新的疾病诊断工具，2）对疾病机制的新工具来改变我们对疾病中疾病在疾病中的作用的理解，3）一种新的能力，以监测疾病症状或反向疾病症状。它还将通过聘用和保留5个新的长期职位以及购买3台主要设备来促进经济刺激。 公共卫生相关性：这项工作与人类健康有关，因为线粒体功能障碍涉及大多数退行性疾病，包括糖尿病，帕金森氏病，亨廷顿氏病和正常衰老。但是，由于我们的工具在体内研究线粒体功能，我们对线粒体功能障碍在这些疾病中的作用的理解存在差距。我们建议为体内线粒体医学创建一个新的转化中心，以进一步开发和扩展我们在体内研究线粒体功能和细胞能量的独特工具。这项新计划将促进对确定能量应力是否会导致细胞适应的条件的新见解，例如在健康组织中，或像疾病状态一样细胞丧失和变性。 这个新中心的目的是使我们的体内方法可以访问更广泛的研究社区，以加速关键突破，并将这些突破转化为临床应用。要求的资金将用于雇用和培训至少五个新的长期职位，并扩大基础设施，以增加我们的实验和分析的吞吐量。