Characterizing novel adult neuronal survival factors

描述（由申请人提供）：神经元的功能和活力通常依赖于分泌的生长因子。尽管在发育中的神经系统中被广泛研究，神经营养因子在成人大脑中是重要的，并且已被检查为成人神经退行性疾病的治疗方式。因此，分离成人大脑中具有神经营养活性的蛋白质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和精神疾病的潜在治疗药物具有广泛的意义。

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.