Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders

神经退行性疾病中的线粒体动力学和代谢组生物标志物

• 批准号: 8216043
• 负责人: Eugenia Trushina
• 金额: $ 30.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8216043
• 关键词: 3-nitropropionic acid; Algorithms; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Biochemical; Biochemical Pathway; Biological Markers; Body Fluids; Calcium; Cell Energetics; Cell model; Cellular biology; Cessation of life; Clinic; Cytoplasm; Data; Defect; Detection; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Design; Early Diagnosis; Environmental Risk Factor; Failure; Fibroblasts; Genetic; Global Change; Goals; Human; Huntington Disease; Hypoxia; In Vitro; Knowledge; Link; Metabolic; Mitochondria; Modeling; Molecular; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidation-Reduction; Paclitaxel; Parkinson Disease; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Play; Prevention; Proteins; Research; Role; Rotenone; Signal Transduction; Stress; Symptoms; Techniques; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Urine; Validation; base; brain tissue; cell motility; cohort; design; disease diagnosis; disorder control; environmental stressor; human HDAC1 protein; in vivo; liquid chromatography mass spectrometry; metabolomics; mitochondrial dysfunction; stressor; therapeutic target; tool development; trafficking

DESCRIPTION (provided by applicant): Disruption of mitochondrial transport, distribution and dynamics arises early in the progression of multiple neurodegenerative disorders caused by environmental and genetic factors, and could be a causative factor in neuronal failure. However, the molecular mechanisms of mitochondrial trafficking inhibition and biomarkers of early mitochondrial dysfunction are undefined. Lack of such knowledge limits development of tools for early diagnosis, monitoring disease progression, and design of efficient therapeutic strategies for neurodegenerative disorders. The objective in this application is using advance technologies to develop an integral panel of mitochondrial/metabolomic biomarkers for early diagnosis of mitochondrial dysfunction in neurodegenerative disorders caused by genetic and environmental factors and to determine molecular mechanism of mitochondrial trafficking inhibition that could be common for multiple diseases. The central hypothesis is that genetic and environmental stressors initiate mitochondrial dysfunction through the common mechanism that involves disruption of mitochondrial dynamics that reflects on and could be detected early by analyzing dynamic alterations in metabolomic signatures and metabolic networks. The rationale for the proposed research is that establishment of mitochondrial and metabolomic signatures as a panel of candidate biomarkers will allow validation in a larger cohort of patients whether these biomarkers could be used for early diagnosis and prediction/monitoring of disease progression. Guided by strong preliminary data, this hypothesis will be tested by pursuing four specific aims: 1) Establish a correlation algorithm between altered parameters of mitochondrial dynamics and signature metabolomic biomarkers in development of mitochondrial dysfunction in neurodegeneration, 2) Validate the use of integral biomarkers of early mitochondrial dysfunction for monitoring the disease progression in trans- genic animal models for AD, HD and PD, and environmental toxicity in vivo, 3) Determine the molecular mechanism of mitochondrial trafficking inhibition induced by environmental and genetic stressors, and 4) Establish the relationship between integral mitochondrial biomarkers and progression of disease in AD, HD and PD patients. Advanced biochemical and cell biology techniques will be applied and combined with the utilization of analytical metabolomic platforms based on 18O-assisted GC/MS, LC/MS/MS, 1H NMR and 18O-assisted 31P NMR technologies to establish the relationship between altered mitochondrial dynamics and metabolomic profiles and global changes in energetic and metabolic signaling circuits in neurons, tissue and body fluids from transgenic animal models and human patients that are associated with Mito dysfunction caused by genetic and environmental stressors. PUBLIC HEALTH RELEVANCE: Mitochondrial dysfunction has been shown to play a central role in progression of multiple neurodegenerative disorders caused by environmental stress and genetic factors. Lack of the under- standing of the molecular mechanisms underlying mitochondrial dysfunction precludes the development of efficient strategies for early diagnosis, prevention and treatment. The proposed study will determine the mechanism by which different genetic and environmental stressors cause mitochondrial dysfunction and will identify relevant metabolomic biomarkers. This study will facilitate understanding of the molecular mechanisms underlying neurodegeneration and promote the development of tools for drug design, diagnosis and disease monitoring.

描述（由申请人提供）：线粒体转运、分布和动力学的破坏出现在由环境和遗传因素引起的多种神经退行性疾病进展的早期，并且可能是神经元衰竭的致病因素。然而，线粒体运输抑制的分子机制和早期线粒体功能障碍的生物标志物是不确定的。缺乏这样的知识限制了早期诊断工具的开发，监测疾病进展，以及设计有效的神经退行性疾病治疗策略。本申请的目的是使用先进技术开发一组完整的线粒体/代谢组学生物标志物，用于早期诊断由遗传和环境因素引起的神经退行性疾病中的线粒体功能障碍，并确定可能常见于多种疾病的线粒体运输抑制的分子机制。核心假设是遗传和环境压力通过共同机制启动线粒体功能障碍，该机制涉及线粒体动力学的破坏，其反映在代谢组学特征和代谢网络中的动态改变，并可以通过分析代谢组学特征和代谢网络中的动态改变来早期检测。拟议研究的基本原理是，将线粒体和代谢组学特征建立为一组候选生物标志物，将允许在更大的患者队列中验证这些生物标志物是否可用于早期诊断和预测/监测疾病进展。在强有力的初步数据的指导下，将通过追求四个具体目标来检验这一假设：1）在神经变性中线粒体功能障碍的发展中，建立线粒体动力学的改变的参数与特征代谢组学生物标志物之间的相关性算法，2）验证早期线粒体功能障碍的积分生物标志物用于监测AD、HD和PD的转基因动物模型中的疾病进展的用途，和体内环境毒性，3）确定由环境和遗传应激源诱导的线粒体运输抑制的分子机制，和4）建立AD、HD和PD患者中完整线粒体生物标志物与疾病进展之间的关系。将应用先进的生物化学和细胞生物学技术，并结合利用基于18 O辅助GC/MS、LC/MS/MS、1H NMR和18 O辅助31 P NMR技术的分析代谢组学平台，以建立改变的线粒体动力学和代谢组学特征与神经元能量和代谢信号通路的整体变化之间的关系，来自转基因动物模型和人类患者的组织和体液，这些组织和体液与由遗传和环境应激源引起的Mito功能障碍有关。 公共卫生关系： 线粒体功能障碍已被证明在由环境应激和遗传因素引起的多种神经退行性疾病的进展中发挥核心作用。缺乏对线粒体功能障碍的分子机制的理解阻碍了早期诊断、预防和治疗的有效策略的发展。这项拟议的研究将确定不同遗传和环境压力导致线粒体功能障碍的机制，并将确定相关的代谢组学生物标志物。这项研究将有助于理解神经退行性变的分子机制，并促进药物设计，诊断和疾病监测工具的开发。