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）：线粒体运输、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一个致病因素。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尚不明确。缺乏这方面的知识限制了早期诊断工具的发展、疾病进展的监测以及神经退行性疾病有效治疗策略的设计。本应用程序的目的是利用先进技术开发线粒体/代谢组学生物标志物的整体小组，用于遗传和环境因素引起的神经退行性疾病中线粒体功能障碍的早期诊断，并确定多种疾病中常见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源通过涉及线粒体动力学破坏的共同机制启动线粒体功能障碍，这反映了可以通过分析代谢组学特征和代谢网络的动态变化来早期检测到。拟议研究的基本原理是，建立线粒体和代谢组学特征作为候选生物标志物，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疾病进展的早期诊断和预测/监测。在强有力的初步数据的指导下，这一假设将通过追求四个具体目标来检验：1)建立线粒体动力学参数改变与特征代谢组学生物标志物在神经退行性疾病线粒体功能障碍发展过程中的关联算法；2)验证早期线粒体功能障碍积分生物标志物在AD、HD和PD转基因动物模型中监测疾病进展和体内环境毒性的应用。3)确定环境和遗传应激源诱导线粒体运输抑制的分子机制；4)建立AD、HD和PD患者线粒体整体生物标志物与疾病进展的关系。将应用先进的生化和细胞生物学技术，并结合基于18o辅助GC/MS、LC/MS/MS、1H NMR和18o辅助31P NMR技术的分析代谢组学平台，建立线粒体动力学和代谢组学特征的改变与神经元能量和代谢信号回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与遗传和环境应激源引起的水户功能障碍有关。