Function of Nna1 in Neuronal Death and Axon Regeneration

Nna1 在神经元死亡和轴突再生中的功能

基本信息

批准号：
8026006
负责人：
JAMES I MORGAN
金额：
$ 36.02万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8026006
关键词：
Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animals Axotomy Binding Binding Sites Biochemical Biological Biological Assay Breeding Carboxypeptidase Categories Cell Death Cell Nucleus Cell Survival Cells Cellular Structures Cerebellum Cessation of life Copy Number Polymorphism Cytoplasm DNA DNA Methylation Diagnosis Disease Double-Stranded RNA Endogenous Retroviruses Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Etiology Event Exhibits GTP Binding Gagging Gene Expression Genes Genetic Genetic Transcription Genome Goals Guanosine Triphosphate HIV Envelope Protein gp120 Health Human Genome Indium Individual Laboratories Lead Lesion Life Expectancy Link Location Mediating Molecular Motor Neurons Mouse Strains Mus Mutant Strains Mice Mutation Natural regeneration Nerve Degeneration Neurodegenerative Disorders Neurons Operative Surgical Procedures Parkinson Disease Pathway interactions Phenotype Phenylalanine Play Point Mutation Process Property Proteins Purkinje Cells RNA Recombinants Research Role Spinal Structure Testing Toxic effect Transcript Transgenic Mice Transgenic Organisms Trauma Tyrosine Viral Wild Type Mouse Zinc age related axon regeneration base eIF-2 Kinase effective therapy env Genes human disease in vivo inhibitor/antagonist insight killings loss of function mutation man mutant neurodegenerative phenotype neuronal survival neurotoxic novel nucleoside triphosphate pol genes promoter prototype regenerative relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): The identification of novel mechanisms that contribute to neuronal survival and the ability of neurons to mount regenerative responses have broad implications for a better understanding and treatment of conditions ranging from neural trauma to a host of neurodegenerative disorders. Here, we focus on Nna1, a protein that represents an unexpected and unique mechanistic link between neuronal death and regeneration. Loss of function mutations in Nna1 lead to neurodegeneration in mice that may be mediated by an unprecedented mechanism that has major implications for neurodegenerative disorders of unknown etiology in man. Nna1 was discovered in the applicant's laboratory as a gene induced in spinal motor neurons following surgical axotomy. In a subsequent collaborative study it was established that mutations in Nna1 caused the neurodegenerative phenotype in the classical autosomal recessive mutant mouse, Purkinje cell degeneration (pcd). Thus, enhanced expression of Nna1 is associated with regenerative responses in the CNS whereas loss-of-function mutations in Nna1 result in neurodegeneration. Recently, the applicant's laboratory demonstrated that Nna1 defined a new subfamily of M14 carboxypeptidases with unique aspects of structure and cellular location. This opens the possibility that genetic lesions that affect these genes may cause degeneration of broader categories of neurons and that endogenous or environmental inhibitors of these enzymes will precipitate neurodegeneration. As the function of Nna1 and the pathway in which it acts are unknown their elucidation will provide new insights into mechanisms of neurodegeneration and regeneration. We have identified a molecular event in pcd mice that is the earliest known deficit in these animals and that may directly link Nna1 to neuronal death. This application proposes three specific aims that will define the biochemical function of Nna1 and its role in neuronal death in cerebellum. These aims will exploit our ability to rescue Purkinje cell loss in pcd3J mutants by re-expressing Nna1 with the L7/pcp2 promoter, our demonstration of the activation of a potentially neurotoxic endogenous retroviral like element in pcd mice and structural information obtained from the identification of a subfamily of novel Nna1-related genes to define the biochemical and cell biological properties of Nna1.

描述（由申请人提供）：鉴定有助于神经元存活的新型机制和神经元安装再生反应的能力具有广泛的影响，对从神经创伤到许多神经退行性疾病的疾病的更好理解和治疗。在这里，我们专注于NNA1，这是一种代表神经元死亡与再生之间意外而独特的机械联系的蛋白质。 NNA1中功能突变的丧失导致小鼠的神经退行性变化，这可能是由一种前所未有的机制介导的，该机制对人类的神经退行性疾病具有重大影响。 NNA1在申请人的实验室中被发现是手术轴切开术后脊柱运动神经元中诱导的基因。在随后的协作研究中，已经确定NNA1中的突变引起了经典常染色体隐性突变小鼠Purkinje细胞变性（PCD）中的神经退行性表型。因此，NNA1的增强表达与中枢神经系统中的再生反应有关，而NNA1中功能丧失突变导致神经变性。最近，申请人的实验室表明，NNA1定义了具有独特的结构和细胞位置方面的M14羧肽酶的新亚家族。这打开了影响这些基因的遗传病变可能会导致更广泛的神经元变性，并且这些酶的内源性或环境抑制剂会导致神经变性。由于NNA1的功能及其作用的途径尚不清楚，其阐明将为神经变性和再生机制提供新的见解。我们已经确定了PCD小鼠中的分子事件，这是这些动物中最早已知的缺陷，它可能直接将NNA1与神经元死亡联系起来。该应用提出了三个特定目标，该目标将定义NNA1的生化功能及其在小脑神经元死亡中的作用。这些目的将利用我们通过用L7/PCP2启动子重新表达NNA1来挽救PCD3J突变体中浦肯野细胞损失的能力。 NNA1。