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Tissue Specific Impact of Organic Cations on Mitochondrial Energy Transduction

有机阳离子对线粒体能量转导的组织特异性影响

基本信息

批准号：
10447580
负责人：
Cameron Alan Schmidt
金额：
$ 2.72万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-08-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447580
关键词：
Address Affect Analytical Biochemistry Applications Grants Area Biochemical Biochemistry Bioenergetics Biology Budgets Carbon Cardiac Cations Cell Death Cell physiology Cells Characteristics Charge Chemicals Chemistry Closure by clamp Cluster Analysis Collection Complex Data Analyses Diabetes Mellitus Disease Doctor of Philosophy Dose Drug Design Drug Interactions Drug Prescriptions Drug Side Effects Drug toxicity Drug usage Educational process of instructing Educational workshop Equipment Exhibits Faculty Fluorometry Free Energy Goals Grant Health Heart Hepatic Hepatobiliary Hydrogen Peroxide Hygiene Impairment In Situ Injury Institutes Knowledge Lead Learning Liver Liver Mitochondria Mathematics Measures Mediator of activation protein Membrane Potentials Mentors Metabolic Metabolism Minor Mitochondria Mitochondrial Proteins Modification Molecular Muscle Mitochondria Nuclear Obesity Organelles Pattern Pharmaceutical Preparations Phenotype Philosophy Physiological Physiology Positioning Attribute Preparation Process Proteins Proteome Proteomics Research Respiration Respiratory System Rodent Sampling Scientist Skeletal Muscle Small Intestines Source Statistical Data Interpretation Statistical Models Structure Structure-Activity Relationship System Systems Biology Technical Expertise Testing Tissues Titrations Toxic effect Training Writing absorption body system design drug metabolism enzyme activity experience experimental study gastrointestinal improved inhibitor interest large datasets lectures medical schools multidisciplinary respiratory response side effect skills student mentoring

项目摘要

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.

项目摘要/摘要药物副作用和更严重的药物损伤是复杂的多因素过程，构成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“第一关”，导致副作用/毒性的不成比例的发生在这些组织中。此外，心脏等高灌注度的组织也不成比例地受到影响。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，突出了这个细胞器作为一个重要的焦点领域。线粒体是因此，线粒体能量转导的微小修改可以导致戏剧性的变化范围从生理功能改变到细胞死亡。新出现的证据表明线粒体从不同的组织中表现出与代谢本质相关的生物能量表型特征对其来源组织的需求。更多证据表明，从不同组织中分离出的线粒体以不同的方式对化学相互作用敏感。这一点很重要，因为这种影响可能是显著的药物副作用/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，我们发现一类常见的药物，有机阳离子(即那些在生理pH下携带净正电荷)，在线粒体中积累高浓度和剂量以(在许多情况下)组织的方式依赖地改变线粒体呼吸和膜电位具体的。从这些观察中，我们得出了一个中心假设，即组织特有的线粒体生物能量表型易于有机阳离子药物和呼吸系统之间的相互作用。至检验这一假设，我们将实施一个整合的工作流程，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的表型能力完成以下研究目标：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.)使用代表性小组测试特定组织的相互作用有机阳离子药物，并定义与相互作用相关的特定蛋白质目标。完成这些目标将解决与驱动的功能和结构相关的关键知识差距受不成比例影响的组织中药物与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为PI(施密特博士)准备过渡到医学院的独立教员职位。培训将在一个最先进的多学科研究所(东卡罗来纳州糖尿病和肥胖研究所)，在一个多样化的指导团队，拥有生理学、生物能量学、生物化学和应用方面的集体经验数学。