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：
8136563
负责人：
PAULO A FERREIRA
金额：
$ 30.31万
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/8136563
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）：线粒体动力学和泛素蛋白酶体系统（UPS）功能的失调是导致严重神经损伤的许多神经退行性和衰老相关疾病发病机制的标志特征。目前促进神经保护的治疗干预措施缺乏治疗效果。我们的长期目标是确定具有新颖的神经保护特性和高治疗功效的靶点，以延缓神经损伤的发作或治愈引起神经损伤的临床表现。为了实现这一目标，我们提出了一个研究项目，其长期目标是更好地理解控制线粒体动力学和 UPS 功能的因素的作用，识别这些因素和过程之间的串扰过程，以及影响）这些因素和过程在神经元存活的调节中。了解控制线粒体动力学或 UPS 活性并有助于调节神经元存活的因素的作用，将使我们和其他人能够创造新的价值目标和治疗策略，以延迟或治愈导致严重神经系统疾病的临床表现的发展损伤。我们将重点确定 RAN GTPase 与其高亲和力和多结合靶点之一 RAN 结合蛋白 2 (RANBP2) 之间的功能关系。该提案测试了我们的总体假设，即 RAN GTPase 与 RANBP2 的 RAN 结合域 -2 和 -3（RBD2 和 RBD3）之间的关联构成了一种新的分子开关，可在 UPS 功能的调节中控制 RANBP2 的效应域，驱动蛋白-1 的线粒体动力学和神经元存活。我们将通过实现以下具体目标来检验这一假设，这些目标重点关注 RanBP2 及其 RBD2 和 RBD3 在正常和疾病应激条件下调节线粒体动力学、蛋白质稳态和选择性神经元存活的机制作用。目标 1. 检验以下假设：RANBP2 的 RBD2 或 RBD3 功能丧失会促进神经元细胞类型之间线粒体运输和存活的不同影响。目标 2. 检验以下假设：RANBP2 的 RBD3 功能丧失会促进神经元细胞类型之间 UPS 活性的差异效应。目标 3. 测试以下假设：在三种应激诱导的神经变性小鼠模型中，RAN GTPase 依赖性调节线粒体运输或 UPS 活性的受损会促进神经保护或选择性神经元的细胞死亡：光诱导的光感受器死亡、高眼压-诱导神经节细胞死亡，MPP+诱导多巴胺能神经元死亡。公共卫生相关性：线粒体运输和控制蛋白质降解机制的失调是导致神经变性的许多神经系统疾病的基础。本研究旨在确定和阐明 RanGTPase 和 Ran 结合蛋白 2 等因子在正常和疾病应激条件下控制线粒体动力学和蛋白质降解以及各种类型神经元存活中的作用。