TETRAHYDROBIOPTERIN BIOSYNTHESIS BY DOPAMINE NEURONS

多巴胺神经元的四氢生物蝶呤生物合成

基本信息

批准号：
2265793
负责人：
GREGORY KAPATOS
金额：
$ 17.14万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-08-01 至 1996-04-30
项目状态：
已结题

项目摘要

Tetrahydrobiopterin is the essential cofactor for tyrosine and tryptophan hydroxylases, the rate-limiting enzymes in the biosynthesis of the monoamine neurotransmitters. Recent evidence also suggests roles for tetrahydrobiopterin in cell proliferation and differentiation. There is unequivocal evidence of inherited deficiencies in human monoamine neurotransmission which are the direct result of genetic defects in tetrahydrobiopterin metabolism. There is suggestive evidence that these genetic defects might also result in abnormal neural development. This competitive renewal outlines a broad series of experiments performed both in culture and in vivo which are designed to further the understanding of the role(s) of tetrahydrobiopterin in the regulation of catecholamine biosynthesis and the development and plasticity of the catecholamine neuron phenotype. Since it is now apparent that there are important differences in the metabolism of tetrahydrobiopterin across specific populations of catecholamine neurons, this objective can only be accomplished by first obtaining a more complete understanding of the nature of these differences. The regulation of cofactor metabolism will thus be studied in dopamine and norepinephrine-containing neurons from the central and peripheral nervous systems maintained in primary tissue culture. The short and long-term interaction between tetrahydrobiopterin and catecholamine biosynthetic systems will be investigated using tissue culture and intact animals with the expectation that these biosynthetic systems are coordinately regulated. The developmental expression and plasticity of the tetrahydrobiopterin phenotype as it relates to catecholamine neurons will also be investigated in tissue culture and in the intact animal. These goals are related in that the interpretation of the interaction between catecholamine and cofactor biosynthetic systems during development and in response to neurotransmitter plasticity will be highly dependent upon the further characterization of their interaction in the mature neuron. It is hoped that these studies will ultimately aid in a better understanding of the etiology of neuropsychiatric disorders and provide different directions for therapeutic approaches in its treatment.

四氢生物蝶呤是酪氨酸和色氨酸的重要辅助因子羟化酶，生物合成中的限速酶单胺类神经递质。最近的证据还表明，四氢生物蝶呤在细胞增殖和分化中的作用。有人类单胺遗传性缺陷的明确证据神经传递是遗传缺陷的直接结果四氢生物蝶呤代谢。有暗示性证据表明这些遗传缺陷也可能导致神经发育异常。这竞争性更新概述了一系列广泛的实验在文化和体内，旨在进一步了解四氢生物蝶呤在儿茶酚胺调节中的作用儿茶酚胺神经元的生物合成以及发育和可塑性表型。由于现在很明显，两者之间存在重要差异四氢生物蝶呤在特定人群中的代谢儿茶酚胺神经元，这个目标只能通过首先实现更全面地了解这些差异的本质。因此，将在多巴胺和辅因子代谢的调节中进行研究来自中枢和周围神经的含有去甲肾上腺素的神经元系统维持在原代组织培养中。短期和长期四氢生物蝶呤与儿茶酚胺生物合成之间的相互作用将使用组织培养和完整的动物来研究系统期望这些生物合成系统得到协调调节。四氢生物蝶呤的发育表达和可塑性与儿茶酚胺神经元相关的表型也将被研究在组织培养和完整动物中。这些目标的相关性在于儿茶酚胺和辅因子之间相互作用的解释发育过程中的生物合成系统以及对神经递质的反应可塑性将高度依赖于进一步表征它们在成熟神经元中的相互作用。希望这些研究能够最终有助于更好地了解该病的病因神经精神疾病并为治疗提供不同的方向其治疗方法。