Regulated Splicing of the Cholinergic Gene Locus

描述（由申请人提供）：本提案的目的是对土壤线虫秀丽隐杆线虫中乙酰胆碱合成和包装进行分子和遗传分析。这些研究集中在两个基因和蛋白质：cha-1是胆碱乙酰转移酶（ChAT）的结构基因，ChAT是合成神经递质乙酰胆碱的酶，unc-17是编码突触囊泡乙酰胆碱转运蛋白（VAChT）的基因; cha-1和unc-17紧密相连，定义了“胆碱能基因座”。一个类似的基因组结构存在于所有的后生动物，到目前为止检查，这表明功能的限制，以维持这种类型的基因组组织。C.由于其简单的神经系统，易于遗传和分子分析，以及方便的DNA介导的转化技术的可用性，线虫被用于这些研究。具体目标包括测试胆碱能转录选择性剪接的模型，并确定参与这种剪接的机制和调节的因素。这些研究的结果将阐明神经末梢内用于协调神经递质供应和需求的机制。 公共卫生相关性：虽然这些研究是基础研究，但它们显然与健康有关，因为乙酰胆碱代谢和/或胆碱能功能的改变已在许多神经系统、神经肌肉和精神疾病中被确定，包括先天性肌无力综合征、阿尔茨海默病和抑郁症。

DESCRIPTION (provided by applicant): The purpose of this proposal is to pursue molecular and genetic analysis of acetylcholine synthesis and packaging in the soil nematode Caenorhabditis elegans. These studies focus on two genes and proteins: cha-1 is the structural gene for choline acetyltransferase (ChAT), the enzyme which synthesizes the neurotransmitter acetylcholine, and unc-17 is the gene which encodes the synaptic vesicle acetylcholine transporter (VAChT); cha-1 and unc-17 are tightly linked and define the "cholinergic gene locus". A similar genomic structure is present in all metazoans thus far examined, suggesting that functional constraints operate to maintain this type of genomic organization. C. elegans is being used for these studies because of its simple nervous system, its ease of genetic and molecular analysis, and the availability of convenient DNA-mediated transformation techniques. The specific aims include testing a model of cholinergic transcript alternative splicing, and identifying factors involved in the mechanism and the regulation of such splicing. The results of these studies will elucidate the mechanisms used within nerve terminals to coordinate neurotransmitter supply and demand. PUBLIC HEALTH RELEVANCE: Although the proposed studies are basic research, they are clearly relevant to health, since alterations in acetylcholine metabolism and/or cholinergic function have been identified in many neurological, neuromuscular, and psychiatric disorders, including congenital myasthenic syndromes, Alzheimer's disease, and depression.