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在多发性神经细胞疾病的进展中早期出现。 退行性疾病是由环境和遗传因素引起的，可能是神经细胞疾病的一个致病因素。 罗纳尔失败。然而，线粒体转运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。这些知识的缺乏限制了早期诊断工具的开发。 SIS，监测疾病进展，并设计有效的神经退行性疾病治疗策略- 德斯。这项应用的目标是使用先进的技术来开发一个完整的丝裂质板- 神经退行性疾病线粒体功能障碍早期诊断的干/代谢生物标志物 由遗传和环境因素引起，并确定线粒体转运的分子机制 ING抑制可能在多种疾病中很常见。中心假设是遗传和环境- 精神应激源通过共同的机制启动线粒体功能障碍，这种机制涉及到 通过分析Me-Me的动态变化，反映并可以早期检测到的线粒体动力学 代谢特征和代谢网络。拟议研究的理由是建立 作为一组候选生物标志物的线粒体和代谢组特征将允许在更大的 这些生物标志物能否用于疾病的早期诊断和预测/监测的患者队列 缓步前进。在强劲的初步数据的指导下，这一假说将通过追求四个具体的 目的：1)建立改变的线粒体动力学参数与信号之间的关联算法 代谢组生物标记物在神经变性线粒体功能障碍发生中的作用，2)验证 早期线粒体功能障碍的积分生物标记物在监测反式-阿尔茨海默病病情进展中的应用 AD、HD和PD的基因动物模型和体内环境毒性，3)确定分子 环境和遗传应激源诱导线粒体转运抑制的机制，以及4)ES- 建立线粒体整体标志物与AD、HD和AD疾病进展的关系 帕金森病患者。我们将应用先进的生化和细胞生物学技术，结合利用 基于~(18)O辅助GC/MS、LC/MS/MS、~1H核磁共振和~(18)O辅助~(31)P的代谢分析平台 核磁共振技术在线粒体动力学改变与代谢组学研究中的应用 神经细胞、组织和体液中能量和代谢信号回路的文件和全球变化 转基因动物模型和人类患者与由基因和基因引起的Mito功能障碍相关 环境应激源。 公共卫生相关性：线粒体功能障碍已被证明在糖尿病的进展中发挥核心作用 环境应激和遗传因素引起的多种神经退行性疾病。缺少底线- 对线粒体功能障碍的分子机制的认识阻碍了效应的发展。 早期诊断、预防和治疗的有效策略。拟议的研究将确定机制- NISM通过不同的遗传和环境应激源导致线粒体功能障碍，并将识别 相关代谢组生物标志物。这项研究将有助于理解在不同环境条件下的分子机制。 促进药物设计、诊断和疾病监测工具的开发。 托林。