Tissue Specific Impact of Organic Cations on Mitochondrial Energy Transduction

项目总结/摘要 药物副作用和更严重的药物引起的损伤是复杂的多因素过程，构成了 处方药使用和设计的重大障碍。胃肠和肝胆系统是 药物吸收和代谢的“首过”，导致副作用/毒性的不成比例发生 在这些组织中。此外，高灌注组织，如心脏，也不成比例地牵连。 越来越多的证据表明，相当大比例的常见药物（约10-40%）可以调节 线粒体能量转导，强调这一细胞器作为一个重要的重点领域。线粒体是 细胞功能的核心，因此，线粒体能量转导的小修改可以导致戏剧性的 从生理功能改变到细胞死亡的变化。新的证据表明线粒体 表现出与代谢相关的生物能量表型特征， 它们的来源组织的需求。其他证据表明，从不同组织中分离的线粒体 以不同的方式对化学反应敏感。这很重要，因为这种影响可能是一个重大的 药物副作用/毒性的组成部分，甚至可能有助于某些药物的主要作用机制。 毒品在我们的初步测试中，我们发现一种常见的药物，有机阳离子（即那些 在生理pH下携带净正电荷），在线粒体中以高浓度积累， 依赖性地改变线粒体呼吸和膜电位的方式是（在许多情况下）组织 特定.根据这些观察，我们提出了一个中心假设，即组织特异性线粒体 生物能量表型使有机阳离子药物和呼吸系统之间的相互作用更易发生。到 为了验证这一假设，我们将实施一个综合工作流程，利用我们独特的线粒体 结合线粒体蛋白质组学和多变量统计分析， 完成以下研究目标：1.）定量定义线粒体结构-功能关系， 胃肠道、肝脏和心脏组织。2.）使用代表性样本组检测组织特异性相互作用 有机阳离子药物和定义特定的蛋白质目标与相互作用。完成 这些目标将解决与功能和结构相关性有关的关键知识缺口， 药物与受不成比例影响的组织中线粒体能量转导系统的相互作用 药物副作用/毒性。随附的培训计划旨在使PI（施密特博士）准备参加 过渡到医学院的独立学术教师职位。培训将在一个 国家的最先进的多学科研究所（东卡罗莱纳糖尿病和肥胖研究所），与支持的一个 多元化的指导团队，在生理学、生物能量学、生物化学和应用 数学

PROJECT SUMMARY/ABSTRACT Drug side effects and more severe drug induced injuries are complex multifactorial processes that pose a significant barrier to prescription drug use and design. The gastrointestinal and hepatobiliary systems are the ‘first pass’ of drug absorption and metabolism, resulting in disproportionate occurrences of side effects/toxicities in these tissues. Additionally, highly perfused tissues, such as the heart, are also disproportionately implicated. Mounting evidence suggests that a substantial proportion of common drugs (~10-40%) can modulate mitochondrial energy transduction, highlighting this organelle as an important area of focus. Mitochondria are central to cellular function, as such, small modifications of mitochondrial energy transduction can lead to dramatic changes ranging from altered physiological function to cell death. Emerging evidence suggests that mitochondria from different tissues exhibit bioenergetic phenotypic characteristics that are intrinsically related to the metabolic demands of their source tissue. Additional evidence suggests that mitochondria isolated from different tissues are sensitive to chemical interactions in distinct ways. This is important because this effect may be a significant component of drug side effects/toxicities and may even contribute to the primary mechanisms of action for some drugs. In our preliminary testing we discovered that a common class of drugs, organic cations (i.e. those that carry a net positive charge at physiological pH), accumulate at high concentrations in mitochondria and dose dependently alter mitochondrial respiration and membrane potential in a manner that is (in many cases) tissue specific. From those observations we developed the central hypothesis that that tissue specific mitochondrial bioenergetic phenotypes predispose interactions between organic cation drugs and the respiratory system. To test this hypothesis, we will implement an integrative workflow that leverages our unique mitochondrial phenotyping capabilities in conjunction with mitochondrial proteomics and multivariate statistical analysis to complete the following research aims: 1.) Quantitatively define mitochondrial structure-function relationships in gastrointestinal, hepatic, and cardiac tissues. 2.) Test for tissue specific interactions using a representative panel of organic cation drugs and define specific protein targets associated with the interactions. The completion of these aims will address a critical knowledge gap pertaining to the functional and structural correlates that drive drug interactions with the mitochondrial energy transduction system in tissues that are disproportionately affected by drug side effects/toxicity. The accompanying training plan is designed to prepare the PI (Dr. Schmidt) for a transition to an independent academic faculty position in a medical school. The training will be carried out in a state-of-the-art multi-disciplinary institute (East Carolina Diabetes and Obesity Institute), with the support of a diverse mentoring team with collective experience in physiology, bioenergetics, biochemistry, and applied mathematics.