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

基本信息

批准号：
8216043
负责人：
Eugenia Trushina
金额：
$ 30.59万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/8216043
关键词：
3-nitropropionic acid Algorithms Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Biochemical Biochemical Pathway Biological Markers Body Fluids Calcium Cell Energetics Cell model 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 Genetic Global Change Goals Human Huntington Disease Hypoxia In Vitro Knowledge Link Metabolic Mitochondria Modeling Molecular Monitor Nerve Degeneration Neurodegenerative Disorders Neurons Oxidation-Reduction Paclitaxel Parkinson Disease Pathogenesis Patients Peripheral Pharmaceutical Preparations Plasma Play Prevention Proteins Research Role Rotenone Signal Transduction Stress Symptoms Techniques Technology Testing Therapeutic Tissues Toxic effect Transgenic Animals Transgenic Mice Transgenic Organisms Urine Validation base brain tissue cell motility cohort design disease diagnosis disorder control environmental stressor human HDAC1 protein in vivo liquid chromatography mass spectrometry metabolomics mitochondrial dysfunction stressor therapeutic target tool development trafficking

项目摘要

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.

描述（由申请人提供）：线粒体转运，分布和动力学的破坏是在由环境和遗传因素引起的多种神经退行性疾病的早期出现的，并且可能是神经元衰竭的原因。但是，线粒体运输抑制和生物标志物的分子机制不确定。缺乏这样的知识限制了早期诊断，监测疾病进展的工具的开发以及神经退行性疾病的有效治疗策略的设计。该应用程序中的目的是使用先进技术来开发线粒体/代谢组生物标志物的整体板，以早期诊断出由遗传和环境因素引起的神经退行性疾病中线粒体功能障碍的早期诊断，并确定多种抑制的分子力学可能是多种疾病的分子力学。中心假设是，遗传和环境应激源通过通用机制启动线粒体功能障碍，涉及破坏线粒体动力学的破坏，这些动力学反映和可以通过分析代谢组学特征和代谢网络的动态变化来早期检测到。拟议的研究的基本原理是，建立线粒体和代谢组学特征作为候选生物标志物小组将允许在较大的患者中进行验证，无论这些生物标志物是否可以用于早期诊断和预测/监测疾病进展。在强大的初步数据的指导下，将通过追求四个具体目的来检验该假设：1）在线粒体动力学的变化参数与签名代谢组合生物标志物之间的变化参数之间建立相关算法，从而在神经变性中开发线粒体功能障碍在神经变性中的开发，2）验证整合性生物标准的使用，2） AD，HD和PD的转基因动物模型的进展以及体内的环境毒性，3）确定通过环境和遗传压力源引起的线粒体运输抑制的分子机制，以及4）建立整体线粒体生物标记和AD，HD和PD患者疾病进展的整体内整体生物标志物之间的关系。高级生物化学和细胞生物学技术将应用并与基于18o辅助GC/MS，LC/MS/MS，1H NMR和18o辅助的31P NMR技术基于基于18o辅助GC/MS，LC/MS/MS的分析代谢组平台的利用并结合使用来自转基因动物模型和人类患者的神经元，组织和体液与遗传和环境压力源引起的MITO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由环境压力和遗传因素引起的多种神经退行性疾病的进展中起着核心作用。缺乏线粒体功能障碍的分子机制缺乏理解，无法开发有效的早期诊断，预防和治疗的策略。拟议的研究将确定不同遗传和环境应激源引起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。这项研究将促进对神经退行性基础的分子机制的了解，并促进用于药物设计，诊断和疾病监测工具的开发。