Genetic and Molecular Dissection of RanBP2-Mediated RanGTPase Functions

RanBP2 介导的 RanGTPase 功能的遗传和分子解析

基本信息

批准号：
8531581
负责人：
PAULO A FERREIRA
金额：
$ 8.59万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531581
关键词：
1-Methyl-4-phenylpyridinium Affinity Age Aging Binding Binding Proteins Biogenesis Cell Death Cells Cessation of life Clinical Development Disease Dissection Goals Guanosine Triphosphate Phosphohydrolases Homeostasis Impairment Kinesin Lead Light Mediating Mitochondria Modeling Molecular Molecular Genetics Mus Nerve Degeneration Neurologic Neurons Neurotoxins Oxidative Stress Pathogenesis Phenotype Photoreceptors Process Property Protein Dynamics Proteins Regulation Research Project Grants Role Running Stress System Testing Therapeutic Intervention Transgenic Mice Treatment Efficacy Ubiquitin age related cell type disease stressor dopaminergic neuron ganglion cell high intraocular pressure improved loss of function loss of function mutation mouse model multicatalytic endopeptidase complex nervous system disorder neuronal survival neuroprotection novel protein degradation public health relevance rat Ran 2 protein sex stressor therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): The deregulation of mitochondria dynamics and function of the ubiquitin-proteasome system (UPS) are hallmark features of the pathogenesis of numerous neurodegenerative and aging-related disorders causing severe neurological impairment. Current therapeutic interventions that promote neuroprotection lack therapeutic efficacy. Our long-term goal is to identify targets with novel neuroprotective properties and high therapeutic efficacies that delay the onset of or cure clinical manifestations causing neurological impairment. To attain this goal we propose a research project whose long-term objective is the development of improved understanding of the role of factors controlling mitochondria dynamics and UPS functions, the identification of cross-talk processes between these factors and processes, and the effect(s) of such factors and processes in modulation of neuronal survival. Understanding the role(s) of factors that control mitochondria dynamics or UPS activity and contribute to the modulation of neuronal survival, would allow us and others to create novel value targets and therapeutic strategies to delay or cure the development of clinical manifestations leading to severe neurological impairments. We will focus on determining the functional relationships between RAN GTPase and one of its high-affinity and multi-binding targets, the RAN-binding protein 2 (RANBP2). This proposal tests our overall hypothesis that the associations between RAN GTPase and, the RAN-binding domains-2 and -3 (RBD2 and RBD3) of RANBP2, constitute a novel molecular switch to control effector domains of RANBP2 in the modulation of UPS function, mitochondria dynamics by kinesin-1, and neuronal survival. We will test this hypothesis by accomplishing the following specific aims, which focus on the mechanistic roles of RanBP2 and its RBD2 and RBD3 in the regulation of mitochondria dynamics, protein homeostasis and survival of selective neurons under normal and disease stress conditions. Aim 1. Test the hypothesis that loss-of-function of the RBD2 or RBD3 of RANBP2 promotes differential effects in mitochondria trafficking and survival among neuronal cell types. Aim 2. Test the hypothesis that loss-of-function of the RBD3 of RANBP2 promotes differential effects in UPS activity among neuronal cell types. Aim 3. Test the hypothesis that impairment of RAN GTPase-dependent modulation of mitochondria trafficking or UPS activity promotes either neuroprotection or cell death of selective neurons in three mouse models of stress-induced neurodegeneration: light-induced death of photoreceptors, high intraocular pressure-induced ganglion cell death, and MPP+induced death of dopaminergic neurons. PUBLIC HEALTH RELEVANCE: The deregulation of trafficking of mitochondria and of the machinery controlling protein degradation underlies numerous neurological disorders leading to neurodegeneration. This study seeks to identify and elucidate the role of factors, such as RanGTPase and Ran-binding protein-2, in controlling mitochondria dynamics and protein degradation and survival of various types of neurons under normal and disease stress conditions.

描述（由申请人提供）：泛素 - 蛋白酶体系统（UPS）的线粒体动力学和功能的放松是众多神经退行性和衰老相关疾病的发病机理的标志性特征，从而导致严重的神经性障碍。促进神经保护的当前治疗干预措施缺乏治疗功效。我们的长期目标是鉴定具有新型神经保护特性和高治疗效率的靶标，这些靶标会延迟或治愈临床表现的发作，从而导致神经系统损害。为了实现这一目标，我们提出了一个研究项目，其长期目标是对控制线粒体动力学和UPS功能的因素的发展，鉴定这些因素和过程之间的串扰过程以及这些因素和过程在神经元存活模型中的影响（S）的影响。了解控制线粒体动力学或UPS活性的因素的作用并有助于调节神经元的生存，这将使我们和其他人能够创建新颖的价值靶标和治疗策略，以延迟或治愈导致严重神经障碍的临床表现的发展。我们将专注于确定RAN GTPase与其高亲和力和多结合靶标之间的功能关系，即RAN结合蛋白2（RANBP2）。该提案检验了我们的总体假设，即RAN GTPase与RANBP2的RAN结合域-2和-3（RBD2和RBD3）之间的关联构成了RANBP2的控制分子转换，以控制RANBP2的RANBP2，在UPS功能，MinochocoChondria Dynamics by Kineinal-1和Neuronal-and Neuronal Servival中，ranbp2构成了RANBP2的控制效应域。我们将通过实现以下特定目标来检验该假设，该目标的重点是RANBP2及其RBD2和RBD3在正常和疾病应激条件下选择性神经元的生存中的调节中的RBD2和RBD3。 AIM 1。检验假设，即RANBP2的RBD2或RBD3的功能丧失会促进线粒体运输和神经元细胞类型中生存的差异作用。 AIM 2。检验以下假设：RANBP2的RBD3功能丧失会促进神经元细胞类型中UPS活性的差异效应。目的3。检验假说，即导致线粒体运输或UPS活性的RAN RAN RAN RAN的损害促进了在胁迫诱导的神经减退的三种小鼠模型中，促进了选择性神经元的神经保护或细胞死亡：光诱导的光感受器的光诱导的光感受器死亡，高核内压神经元素诱导的神经节诱导的死亡和M诱导的抑制剂+M M+M M+MM drogin+MM。公共卫生相关性：线粒体贩运和控制蛋白质降解的机制的管制是导致神经变性的许多神经系统疾病的基础。这项研究旨在识别和阐明因素（例如rangtpase和Ran结合蛋白2）在控制正常和疾病压力条件下各种神经元的蛋白质降解以及蛋白质降解以及蛋白质降解和存活中的因素的作用。