Characterizing novel adult neuronal survival factors

表征新的成人神经元存活因素

基本信息

批准号：
7539161
负责人：
JAMES I MORGAN
金额：
$ 32.89万
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：
2004
资助国家：
美国
起止时间：
2004-12-10 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7539161
关键词：
AMPA Receptors Accounting Adult Affect Amino Acid Motifs Ataxia Behavioral Binding Sites Biochemical Biological Brain Cell Survival Cerebellum Cleaved cell Complex Cytoplasmic Granules Data Data Set Databases Defect Event Family Fiber Financial compensation Genes Genetic Glutamate Receptor Glycoproteins Goals Growth Factor Hemolysin Integral Membrane Protein Knock-out Knockout Mice Laboratories Location Long-Term Depression Maintenance Mediating Membrane Mental disorders Messenger RNA Methods Modality Molecular Mus Nature Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurologic Neurons Orphan Pathway interactions Peptide Hydrolases Phenotype Physiological Principal Investigator Process Property Protein Family Proteins Proteolysis Proteolytic Processing Purkinje Cells Signal Pathway Signal Transduction Site Structure Synapses Synaptic Transmission Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Tumor Necrosis Factor-alpha Tumor Necrosis Factors base disulfide bond functional disability glutamate receptor delta 2 glycosylation granule cell homologous recombination information processing man mimicry neuron loss neuronal survival neuropsychiatry neurotrophic factor novel null mutation postsynaptic presynaptic programs prototype receptor relating to nervous system trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): The function and viability of neurons is frequently dependent upon secreted growth factors. Although most extensively investigated in the developing nervous system neurotrophic factors are important in the adult brain and have been examined as therapeutic modalities in adult neurodegenerative conditions. Therefore, the isolation of proteins in adult brain with neurotrophic activity could have broad implications both for our understanding of the maintenance of neuronal integrity and function in the mature nervous system and as potential therapeutic agents for a range of neurological and psychiatric disorders. We identified a family of brain-specific proteins (Cbln1-Cbln4), termed synaptotrophins that have properties of adult neurotrophic factors. Cbln1 and Cbln3 are secreted glycoproteins that are co-expressed in mature cerebellar granule cells and form trimeric complexes that are structurally related to tumor necrosis factor-alpha (TNFalpha). Elimination of Cbln1 through homologous recombination in mice causes ataxia, marked structural and physiological defects in granule celI-Purkinje cell synaptic interactions and the progressive degeneration of adult cerebellar granule neurons. Thus Cbln1 is the prototype of a novel class of factor that regulates synaptic stability and function and neuronal survival. Remarkably, loss of the orphan glutamate delta2 receptor (GluRdelta2) in Purkinje cells mimics the phenotype of the cbln1-null mouse. Thus, presynaptic Cbln1 and postsynaptic GluRdelta2 may be components of a novel trophic signaling pathway. This mechanism likely exists elsewhere in brain having implications for neuropsychiatric (disrupted synaptic transmission) and neurodegenerative disorders (neuronal loss and functional impairment) in man. In this application we take advantage of the structural and functional properties of TNFalpha and GluRdelta2 to elucidate the molecular bases of the neural deficits in cbln1-null mice and characterize the components of the Cbln1 signaling pathway.

描述（由申请人提供）：神经元的功能和生存能力通常取决于分泌的生长因子。尽管在发育中的神经系统神经营养因素中最广泛的研究在成人大脑中很重要，并且已被视为成人神经退行性疾病的治疗方式。因此，具有神经营养活性的成年大脑中蛋白质的分离可能对我们理解成熟神经系统中神经元完整性和功能的维持以及作为一系列神经系统和精神疾病的潜在治疗剂。我们确定了一个脑特异性蛋白（CBLN1-CBLN4）家族，该蛋白质称为突触营养素，具有成年神经营养因子的特性。 CBLN1和CBLN3是分泌的糖蛋白，它们在成熟的小脑颗粒细胞中共表达，并形成与肿瘤坏死因子因子-Alpha（TNFalpha）结构相关的三聚体复合物。通过小鼠共济失调，通过同源重组消除CBLN1，颗粒旋转旋转粉状细胞突触相互作用的结构和生理缺陷以及成年小脑颗粒神经元的进行性变性。因此，CBLN1是调节突触稳定性和功能以及神经元存活的新型因子的原型。值得注意的是，珀kinje细胞中孤儿谷氨酸藻酸酯受体（Glurdelta2）的丧失模仿CBLN1-NULL小鼠的表型。因此，突触前CBLN1和突触后Glurdelta2可能是新型营养信号通路的组成部分。这种机制可能存在于大脑其他地方，对人类的神经精神病学（突触传播）和神经退行性疾病（神经元丧失和功能障碍）具有影响。在此应用中，我们利用TNFalpha和Glurdelta2的结构和功能特性来阐明CBLN1-NULL小鼠中神经缺陷的分子碱基，并表征CBLN1信号通路的成分。