Microtubule regulation of nuclear trafficking in oxidatively-stressed neurons

氧化应激神经元核运输的微管调节

基本信息

批准号：
8199680
负责人：
Vivek Prashant Patel
金额：
$ 3.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8199680
关键词：
1-Methyl-4-phenylpyridinium Acetylation Address Affect Age Alzheimer&apos s Disease Amyloid Autopsy Axonal Transport Binding Biochemistry Catecholamines Child Chronic Data Defect Development Disease Disease model Dynein ATPase Elderly Functional disorder Future Gene Expression Genes Genetic Growth Health Human Huntington Disease Hydroxydopamines Image Impairment Injury Kinesin LRRK2 gene Lead Length Life Literature Maintenance Microtubule Alteration Microtubules Modeling Modification Molecular Biology Molecular Motors Motor Nerve Degeneration Neurites Neurodegenerative Disorders Neuronal Dysfunction Neuronal Injury Neurons Neurotransmitters Nuclear Oxidation-Reduction Oxidative Stress Parkinson Disease Pathogenesis Pathway interactions Plus End of the Microtubule Population Post-Translational Protein Processing Primary Lateral Sclerosis Process Proteins Quality of life Regulation Research Proposals Rotenone Signal Transduction Stress Substantia nigra structure Synapses System Techniques Toxin Training Tubulin analog base cellular imaging effective therapy gene repair polarized cell pre-doctoral response trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Neurodegenerative diseases affect the quality of life for a significant amount of the population, ranging from children to the elderly. Not much is known regarding the causes of this class of diseases, making the approach towards effective therapies difficult. Pathways involved in neurodegeneration include oxidative stress, synaptic dysfunction, and altered gene expression. This research proposal focuses on the interplay between these pathways through the study of microtubule function. The specific mechanisms causing transcriptional alterations observed in neurodegenerative disorders, such as Parkinson's disease, are yet to be elucidated; however a potential mechanism involves alterations of microtubule function. Increasing evidence of dysfunction in microtubule-dependent processes is being found in neurodegenerative diseases - suggesting it as a common mechanism underlying neuronal degeneration. This research proposal examines if specific regulatory changes in the microtubule network in oxidatively- stressed neurons might impact efficiency of processes such as transcription factor trafficking and neurite remodeling. Techniques in molecular biology, biochemistry, and imaging will be employed to address these questions. Aim 1 will examine neuronal microtubule dynamics in response to oxidative injury via live-cell imaging and Aim 2 will examine the effects of oxidative neuronal injury on microtubule post-translational modifications and binding of molecular motors. Both aims will further examine the effects of oxidative modulations in microtubule function on transcription factor trafficking and neurite maintenance. In addition to providing predoctoral training to the applicant, this research proposal will help elucidate mechanisms that lead to neuronal degeneration, which will aid in the development of future neuroprotective strategies. PUBLIC HEALTH RELEVANCE: Neurodegenerative disorders, such as Parkinson's disease, affect the quality of life for a significant amount of the population and are becoming even a greater concern as the U.S. population ages. Elucidating the mechanisms that lead to neuronal dysfunction and degeneration in these disorders will help in the development of future neuroprotective strategies.

描述（由申请人提供）：神经退行性疾病影响大量人群（从儿童到老年人）的生活质量。关于此类疾病的原因知之甚少，这使得寻找有效的治疗方法变得困难。神经变性涉及的途径包括氧化应激、突触功能障碍和基因表达改变。该研究计划通过微管功能的研究重点关注这些途径之间的相互作用。在帕金森病等神经退行性疾病中观察到的导致转录改变的具体机制尚未阐明。然而，一个潜在的机制涉及微管功能的改变。在神经退行性疾病中发现了越来越多的微管依赖性过程功能障碍的证据，表明它是神经元变性的常见机制。该研究计划检查氧化应激神经元中微管网络的特定调节变化是否可能影响转录因子运输和神经突重塑等过程的效率。将采用分子生物学、生物化学和成像技术来解决这些问题。目标 1 将通过活细胞成像检查神经元微管动态响应氧化损伤，目标 2 将检查氧化神经元损伤对微管翻译后修饰和分子马达结合的影响。这两个目标都将进一步研究微管功能的氧化调节对转录因子运输和神经突维持的影响。除了为申请人提供博士前培训外，该研究计划还将有助于阐明导致神经元变性的机制，这将有助于制定未来的神经保护策略。公共健康相关性：神经退行性疾病，如帕金森病，影响大量人口的生活质量，并且随着美国人口老龄化而变得更加令人担忧。阐明导致这些疾病的神经元功能障碍和退化的机制将有助于制定未来的神经保护策略。