Integrative Investigation of Mitochondrial Dysfunction

线粒体功能障碍的综合研究

• 批准号: 8191866
• 负责人: FADI GABRIEL AKAR
• 金额: $ 16.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191866
• 关键词: Action Potentials; Address; Adenine; Adverse effects; Affect; Agonist; Anions; Arrhythmia; Behavior; Benzodiazepine Receptor; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Coupled; Coupling; Dependence; Differentiation and Growth; Disease; Disease Progression; Electron Transport; Energy-Generating Resources; Equilibrium; Eukaryotic Cell; Exhibits; Functional disorder; Future; Gene Silencing; Gene Transfer; Generations; Heart; Heart Diseases; Heart Hypertrophy; Image; Imaging Techniques; In Vitro; Intervention; Investigation; Kinetics; Lead; Left Ventricular Hypertrophy; Link; Measurement; Measures; Mechanics; Mediating; Membrane; Membrane Potentials; Mental disorders; Metabolic; Mission; Mitochondria; Modeling; Muscle Cells; National Heart, Lung, and Blood Institute; Organ; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Physiological; Plant Roots; Predisposition; Process; Production; Property; Protons; Pump; Reactive Oxygen Species; Recovery; Regulation; Resolution; Risk; Role; Seminal; Signal Pathway; Signal Transduction; Superoxides; Surface; Work; adenoviral-mediated; electrical property; inhibitor/antagonist; insight; meetings; mitochondrial dysfunction; mitochondrial membrane; mortality; nervous system disorder; novel; overexpression; oxidation; pressure; prevent; receptor; receptor expression; regenerative; response; stressor; tripolyphosphate

DESCRIPTION (provided by applicant): The mitochondrial membrane potential (DYm) is a key regulator of mitochondrial function that drives the production of ATP and reactive oxygen species (ROS). Dynamic oscillations of DYm in isolated cardiac myocytes can result in electrophysiological oscillations that significantly impact myocyte function and lead to inexcitability at the cellular level. However, technical challenges in measuring spatio-temporal gradients in metabolic function within the intact heart have precluded a direct investigation of the functional consequences of unstable mitochondrial properties in mediating global oxidative stress and associated mechano-electrical dysfunction. Since the original submission of this proposal, we have developed a semi-quantitative imaging technique for measuring the spatio-temporal dynamics of DYm with subcellular resolution at the organ level. In this proposal, we extend our measurements to perform ROS imaging in order to investigate if ROS-induced ROS-release is a mechanism of DYm instability within the intact normal and hypertrophied heart. Previous work identified the mitochondrial benzodiazepine receptor (mBZR) as a potentially attractive candidate for preventing arrhythmias. However, pharmacological interventions that target mBzR significantly impact contractile and calcium handling properties by directly suppressing the L-type calcium current. This may limit the clinical utility of these agents and raises important questions regarding the direct relevance of DYm stability per se in altering mechano-electrical properties. We will directly address this important issue by using a gene transfer approach that targets mBZR expression. This will uncover the role of IMAC through mBZR overexpression in altering mitochondrial, mechanical, and electrical properties. From a practical perspective, these studies will help us determine if modulation of mBZR expression is a viable strategy for altering mechano-electrical properties. If so, future gene silencing to mimic IMAC blockade may be warranted. PUBLIC HEALTH RELEVANCE: This proposal is dedicated to: 1) developing integrative imaging techniques to uncover mechanisms by which altered metabolic properties in cardiac hypertrophy predispose to electrical and contractile dysfunction; and 2) using gene transfer approaches to modulate electrical and contractile properties by regulating mitochondrial function through the expression levels of a key receptor.

描述（由申请人提供）：线粒体膜电位（DYM）是线粒体功能的关键调节剂，可驱动ATP和活性氧（ROS）的产生。 DYM在分离的心肌细胞中的动态振荡会导致电生理振荡，从而显着影响心肌细胞功能并导致细胞水平的不可思议。然而，在完整心脏中测量代谢功能中的时空梯度方面的技术挑战已经直接研究了不稳定的线粒体特性在介导整体氧化应激和相关机械 - 电动功能障碍中的功能后果。自从该提案的最初提交以来，我们开发了一种半定量成像技术，用于测量DYM的时空动力学，并在器官水平下进行亚细胞分辨率。在此提案中，我们将测量值扩展到进行ROS成像，以研究ROS诱导的ROS-释放是否是完整正常和肥大心脏内DYM不稳定性的机制。先前的工作将线粒体苯二氮卓受体（MBZR）确定为预防心律不齐的潜在吸引人的候选者。但是，针对MBZR的药理干预措施通过直接抑制L型钙电流来显着影响收缩和钙处理特性。这可能会限制这些药物的临床实用性，并提出有关DYM稳定性本身直接相关性在改变机械特性的直接相关性的重要问题。我们将使用针对MBZR表达的基因转移方法直接解决这一重要问题。这将发现iMac通过MBZR过表达在改变线粒体，机械和电性能中的作用。从实际的角度来看，这些研究将有助于我们确定MBZR表达的调节是否是改变机械电特性的可行策略。如果是这样，则可能有必要对未来的基因沉默到模仿iMac封锁。 公共卫生相关性：该提案致力于：1）开发整合成像技术以发现机制，通过这种机制，通过这种机制，心脏肥大中的代谢特性倾向于易受电气和收缩功能障碍； 2）使用基因转移方法通过通过关键受体的表达水平调节线粒体功能来调节电和收缩性能。