MOLECULAR GENETICS OF BIOGENIC AMINE NEURONS

本文提出的实验旨在进一步我们的 了解单胺神经元的发育和功能， 神经系统中的一元胺 神经递质水平异常 和单胺神经元的缺陷 与许多人类病理（例如帕金森病， 苯酮脲、精神分裂症等）。 长期目标 拟议的研究是开发遗传变异， 分子探针可以操纵生物胺 在模型系统中，黑腹果蝇的合成，对于每个 胺（血清素，多巴胺和章鱼胺），并扰乱 单胺神经元的递质表型 新的基因变异。 生物学后果 胺水平和胺特异性的扰动 单个神经元亚群将在常规的神经元亚群中进行分析。 和新的遗传变异。 特别是分子遗传学 编码色氨酸羟化酶、酪氨酸羟化酶和 酪胺β羟化酶将被开发，因此它将被 可以操纵每种胺的合成， 克隆可赋予细胞类型特异性表达的序列， 和表征了 这些目标将通过以下方式实现： 实验策略依赖于分子和遗传 方法，其中许多是果蝇独有的。 这些 方法将与当前的 解剖学、组织化学、生物化学和免疫组织化学 方法。 这里开发的分子探针和遗传变异 将增强和补充目前的细胞和生化 了解到目前为止最好的特征神经元集， 神经系统

The experiments proposed herein are designed to further our understanding of development and function of monoamine neurons and monoamines in the nervous system. Aberrant neurotransmitter levels and defects in monoamine neurons have been observed in association with a number of human pathologies (e.g. Parkinson's disease, phenylketoneurea, schizophrenia etc.). The long term objectives of the proposed research are to develop genetic variants and molecular probes that will allow manipulation of the biogenic amine synthesis in the model system, Drosophila melanogaster, for each amine (serotonin, dopamine and octopamine), and to perturb the transmitter phenotype of monoamine containing neurons by creation of novel genetic variants. Biological consequences of perturbations in amine level and amine specificity for each individual neuronal subsets will be analyzed in the conventional and novel genetic variants. Specifically molecular genetics of genes encoding tryptophan hydroxylase, tyrosine hydroxylase and tyramine beta hydroxylase will be developed, so that it will be possible to manipulate synthesis of each amine, and promoter sequences that can confer cell type specific expression are cloned and characterized. These goals will be approached using experimental strategies that depend on molecular and genetic methodologies, many of which are unique to Drosophila. These methodologies will be used in conjunction with the current anatomical, histochemical, biochemical and immunohistochemical approaches. Molecular probes and genetic variants developed here will augment and complement the current cellular and biochemical understanding of by far the best characterized set of neurons in the nervous system.