Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders

项目总结/摘要 线粒体转运、分布和动力学的破坏出现在多发性神经细胞瘤进展的早期， 由环境和遗传因素引起的退行性疾病，可能是神经退行性疾病的致病因素。 ronal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， 线粒体功能障碍尚未明确。缺乏这种知识限制了早期诊断工具的发展。 SIS、监测疾病进展和设计有效治疗神经退行性疾病策略， ders。该应用的目标是利用先进技术开发线粒体的整体面板- 用于神经退行性疾病中线粒体功能障碍早期诊断的线粒体/代谢组学生物标志物 引起的遗传和环境因素，并确定线粒体运输的分子机制， 这可能是多种疾病的共同抑制。核心假设是，遗传和环境- 精神压力源通过破坏线粒体功能的共同机制启动线粒体功能障碍， 线粒体动力学反映并可以通过分析线粒体中的动态变化来早期检测， Tabolomic签名和代谢网络。拟议研究的理由是， 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。 这些生物标志物是否可用于疾病的早期诊断和预测/监测。 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 目的：1）建立线粒体动力学参数变化与信号特征之间的关联算法 代谢组学生物标志物在神经退行性疾病中线粒体功能障碍的发展，2）证实 使用早期线粒体功能障碍的完整生物标志物监测反式- AD、HD和PD的基因动物模型，以及体内环境毒性，3）确定分子水平， 环境和遗传应激诱导的线粒体运输抑制机制，以及4）Es- 建立完整的线粒体生物标志物与AD、HD和 PD患者。我们将应用先进的生物化学和细胞生物学技术， 基于18 O辅助GC/MS、LC/MS/MS、1H NMR和18 O辅助31 P的分析代谢组学平台 核磁共振技术，以建立改变线粒体动力学和代谢组学前体之间的关系， 神经元、组织和体液中的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遗传和 环境压力源

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.