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: 8691816
• 负责人: Eugenia Trushina
• 金额: $ 30.29万
• 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/8691816
• 关键词: 3-nitropropionic acid; Affect; Algorithms; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Biochemical; Biochemical Pathway; Biological Markers; Body Fluids; Calcium; Cell Energetics; Cell model; Cells; 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; Functional disorder; Genetic; Global Change; Goals; Human; Huntington Disease; Hypoxia; Image; In Vitro; Knowledge; Link; Metabolic; Mitochondria; Modeling; Molecular; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcomes Research; Oxidation-Reduction; Paclitaxel; Parkinson Disease; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Play; Prevention; Proteins; Psyche structure; Research; Role; Rotenone; Signal Transduction; Stress; Symptoms; Techniques; Technology; Testing; Therapeutic; Tissues; Toxic effect; Toxin; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Urine; Validation; abstracting; base; brain tissue; cell motility; cohort; design; disease diagnosis; disorder control; environmental stressor; human HDAC1 protein; human tissue; in vivo; liquid chromatography mass spectrometry; metabolomics; mitochondrial dysfunction; novel; public health relevance; stressor; therapeutic target; tool development; trafficking

Project Summary/Abstract Disruption of mitochondrial transport, distribution and dynamics arises early in the progression of multiple neu- rodegenerative disorders caused by environmental and genetic factors, and could be a causative factor in neu- ronal 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 diagno- sis, monitoring disease progression, and design of efficient therapeutic strategies for neurodegenerative disor- ders. The objective in this application is using advance technologies to develop an integral panel of mitochon- drial/metabolomic biomarkers for early diagnosis of mitochondrial dysfunction in neurodegenerative disorders caused by genetic and environmental factors and to determine molecular mechanism of mitochondrial traffick- ing inhibition that could be common for multiple diseases. The central hypothesis is that genetic and environ- mental 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 me- tabolomic 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 dis- ease 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) Es- tablish the relationship between integral mitochondrial biomarkers and progression of disease in AD, HD and PD patients. We will apply advanced biochemical and cell biology techniques combined with utilization of the 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 pro- files 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 effi- cient strategies for early diagnosis, prevention and treatment. The proposed study will determine the mecha- nism 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 under- lying neurodegeneration and promote the development of tools for drug design, diagnosis and disease moni- toring.

项目摘要/摘要 线粒体运输，分布和动力学的破坏是在多个neu-的发展中出现的 由环境和遗传因素引起的繁殖疾病 罗纳尔失败。但是，线粒体运输抑制和早期生物标志物的分子机制 线粒体功能障碍是未定义的。缺乏这种知识限制了早期诊断工具的开发 - SIS，监测疾病进展和设计有效的治疗策略，用于神经退行性疾病 der。本应用程序中的目的是使用先进的技术来开发线条的整体面板 - DRIAL/代谢组生物标志物，用于早期诊断神经退行性疾病中线粒体功能障碍 由遗传和环境因素引起，并确定线粒体贩运的分子机制 抑制可能是多种疾病常见的。中心假设是遗传和环境 精神压力源通过涉及破坏的共同机制引发线粒体功能障碍 通过分析ME的动态变化来反映并可以早期检测到的线粒体动力学 tabolomic签名和代谢网络。拟议研究的理由是建立 线粒体和代谢组签名作为候选生物标志物的面板将允许在较大的验证中进行验证 患者的队列是否可以用于早期诊断和预测/监测疾病 放松进展。在强大的初步数据的指导下，该假设将通过追求四个特定的特定来检验 目的：1）在线粒体动力学和签名变化参数之间建立相关算法 神经变性中线粒体功能障碍发展中的代谢组生物标志物，2）验证 使用早期线粒体功能障碍的整体生物标志物来监测跨性别的疾病进展 AD，HD和PD的基因动物模型以及体内的环境毒性，3）确定分子 环境和遗传压力诱导的线粒体运输抑制机制，4）ES- 使线粒体生物标志物与AD，HD和HD和 PD患者。我们将采用高级生化和细胞生物学技术，结合使用 基于18o辅助GC/MS，LC/MS/MS，1H NMR和18O辅助31p的分析代谢组平台 NMR技术建立了改变线粒体动力学与代谢组学方面的关系 来自神经元，组织和体液中的能量和代谢信号电路的档案和全球变化 转基因动物模型和与MITO功能障碍有关的转基因动物模型和由遗传和 环境压力源。 公共卫生相关性：线粒体功能障碍已被证明在进展中起着核心作用 由环境压力和遗传因素引起的多种神经退行性疾病。缺乏 线粒体功能障碍的分子机制的站立无法促进 早期诊断，预防和治疗的有效策略。拟议的研究将确定机械 不同的遗传和环境压力源引起线粒体功能障碍并将确定 相关代谢组生物标志物。这项研究将促进对低下的分子机制的理解 撒谎神经变性并促进制定药物设计，诊断和疾病工具的开发 校园。