Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders

描述(申请人提供)：线粒体运输、分布和动力学的中断在由环境和遗传因素引起的多种神经退行性疾病的进展过程中早期出现，并可能是神经元衰竭的原因之一。然而，线粒体转运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清楚。缺乏这样的知识限制了早期诊断、监测疾病进展和设计有效的神经退行性疾病治疗策略的工具的开发。这项应用的目的是利用先进的技术开发一套完整的线粒体/代谢组生物标志物，用于早期诊断由遗传和环境因素引起的神经退行性疾病中的线粒体功能障碍，并确定多种疾病常见的线粒体转运抑制的分子机制。核心假设是，遗传和环境应激源通过共同的机制启动线粒体功能障碍，该机制涉及线粒体动力学的破坏，通过分析代谢组特征和代谢网络的动态变化可以及早发现。拟议研究的基本原理是，建立线粒体和代谢组特征作为一组候选生物标记物，将允许在更大的患者队列中验证这些生物标记物是否可以用于疾病进展的早期诊断和预测/监测。在强大的初步数据的指导下，这一假说将通过以下四个具体目标进行验证：1)建立神经退行性变中线粒体功能障碍发生过程中线粒体动力学参数变化和特征代谢组生物标志物之间的关联算法；2)验证早期线粒体功能障碍的整合生物标志物在监测AD、HD和PD转基因动物模型中的疾病进展以及体内环境毒性方面的作用；3)确定环境和遗传应激源诱导的线粒体运输抑制的分子机制；以及4)建立完整的线粒体生物标志物与AD、HD和PD患者疾病进展之间的关系。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核磁共振和18O辅助31P核磁共振技术的分析代谢组平台，建立线粒体动力学和代谢组谱的改变与转基因动物模型和人类患者的神经元、组织和体液中能量和代谢信号通路的全球变化之间的关系，这些变化与遗传和环境应激导致的线粒体功能障碍有关。 公共卫生相关性： 线粒体功能障碍已被证明在环境应激和遗传因素引起的多种神经退行性疾病的进展中起核心作用。由于缺乏对线粒体功能障碍的分子机制的了解，阻碍了早期诊断、预防和治疗的有效策略的发展。这项拟议的研究将确定不同的遗传和环境应激源导致线粒体功能障碍的机制，并将确定相关的代谢组生物标志物。这项研究将有助于了解神经退行性变的分子机制，并促进药物设计、诊断和疾病监测工具的开发。

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.