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.

项目概要/摘要 线粒体运输、分布和动力学的破坏出现在多种神经元疾病进展的早期。 由环境和遗传因素引起的退行性疾病，可能是神经系统疾病的致病因素 罗纳尔失败。然而，线粒体运输抑制的分子机制和早期的生物标志物 线粒体功能障碍尚不明确。缺乏这些知识限制了早期诊断工具的开发 sis，监测疾病进展，并设计神经退行性疾病的有效治疗策略 德斯。本申请的目标是利用先进技术开发线粒体的完整面板 用于神经退行性疾病线粒体功能障碍早期诊断的实验/代谢组生物标志物 由遗传和环境因素引起并确定线粒体运输的分子机制 抑制可能对多种疾病很常见。中心假设是遗传和环境 精神压力源通过破坏线粒体的共同机制引发线粒体功能障碍。 线粒体动力学反映并可以通过分析线粒体的动态变化来早期检测到 分类学特征和代谢网络。拟议研究的基本原理是建立 线粒体和代谢组学特征作为一组候选生物标志物将允许在更大范围内进行验证 患者队列是否可以使用这些生物标志物进行早期诊断和预测/监测疾病 缓解进展。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的 目标：1）建立线粒体动力学改变参数和特征之间的相关算法 神经变性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反式疾病进展 AD、HD 和 PD 的基因动物模型以及体内环境毒性，3) 确定分子 环境和遗传应激源诱导的线粒体运输抑制机制，以及 4) Es- 建立了 AD、HD 和 AD 患者的完整线粒体生物标志物与疾病进展之间的关系 帕金森病患者。我们将应用先进的生化和细胞生物学技术并结合利用 基于 18O 辅助 GC/MS、LC/MS/MS、1H NMR 和 18O 辅助 31P 的分析代谢组学平台 NMR 技术可建立改变的线粒体动力学与代谢组学亲之间的关系 神经元、组织和体液中能量和代谢信号通路的文件和全局变化 与由遗传和遗传因素引起的 Mito 功能障碍相关的转基因动物模型和人类患者 环境压力源。 公共卫生相关性：线粒体功能障碍已被证明在疾病进展中发挥核心作用 由环境压力和遗传因素引起的多种神经退行性疾病。缺乏下层 线粒体功能障碍的分子机制的地位阻碍了效率的发展 早期诊断、预防和治疗的科学策略。拟议的研究将确定机械 不同的遗传和环境压力因素导致线粒体功能障碍的观点，并将识别 相关代谢组生物标志物。这项研究将有助于理解以下分子机制： 神经退行性疾病并促进药物设计、诊断和疾病监测工具的开发 撕裂。