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PROTEIN NEUROTRANSMISSION AND BEHAVIOR

蛋白质神经传递和行为

基本信息

批准号：
3380068
负责人：
J STEVE KIZER
金额：
$ 13.94万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-07-01 至 1989-11-30
项目状态：
已结题

项目摘要

Protein neurotransmitters are involved in initiating and maintaining complex behaviors in mammals. Furthermore, abnormalities of protein neurotransmission will undoubtedly be found to underlie some neuropsychiatric illness. The development of models to study abnormal protein neurotransmission and the correlation of these models with clinical disease, however, has been impeded by the lack of clinically or experimentally useful drugs to modify protein neurotransmission and by the lack of clinical methods to evaluate protein neurotransmission in the behaviorally disturbed. The purpose of this proposal is two-fold: First, basic investigations into posttranslational processing of peptide neurotransmitters in the central nervous system; and second, a search for evidence of abnormal protein neurotransmission in the behaviorally and cognitively disabled. The first project will include basic, biochemical studies of peptide amidation, N-terminal glutaminyl cyclization, and the posttranslational processing of the presursor for TRH. This project is concerned with isolation, purification, definition of the catalytic mechanisms, immunocytochemical localization and the physiological regulation of the enzymes catalyzing these posttranslational modifications. The third aspect of this project, studies of the posttranslational processing of TRH precursor, is intended to serve as a model for studies of those special neuronal adaptations required to maintain adequate stores of protein neurotransmission in distal nerve terminals. The second major program will determine whether a constitutional deficiency or abnormality in posttranslational processing may be associated with mental retardation, affective disorder or psychosis in young and old adults who are either severely mentally disabled or psychiatrically ill. Serum levels of peptidyl glycine monooxygenase and glutamine cyclotransferase will be determined in these types of patients and correlated with their clinical illness. Methods involved in this research will include high pressure liquid chromatography, radioimmunoassay, generation of antisera, amino acid analysis, mass spectroscopy, immunoaffinity chromatography, gel chromatography, fast protein liquid chromatography, isoelectric focusing, thin layer chromatography, and solid phase and liquid protein synthetic chemistry.

蛋白质神经递质参与启动和维持哺乳动物的复杂行为。此外，蛋白质异常毫无疑问，神经传递将被发现是某些现象的基础神经精神疾病。研究异常的模型的开发蛋白质神经传递以及这些模型与临床的相关性然而，由于缺乏临床或实验上有用的药物来改变蛋白质神经传递并通过缺乏评估蛋白质神经传递的临床方法行为上受到干扰。该提案的目的有两个：第一，肽翻译后加工的基础研究中枢神经系统的神经递质；其次，搜索行为和行为方面异常蛋白质神经传递的证据认知障碍。第一个项目将包括基础、生化肽酰胺化、N-末端谷氨酰胺酰环化和 TRH 前体的翻译后加工。这个项目是涉及催化的分离、纯化、定义机制、免疫细胞化学定位和生理学催化这些翻译后酶的调节修改。本项目的第三个方面，研究 TRH 前体的翻译后加工旨在充当研究那些特殊神经元适应所需的模型维持远端神经中足够的蛋白质神经传递储存终端。第二个主要计划将决定是否翻译后加工的体质缺陷或异常可能与精神障碍、情感障碍或精神病有关患有严重精神障碍或患有严重精神障碍的年轻人和老年人患有精神疾病。肽基甘氨酸单加氧酶和血清水平将在这些类型的患者中测定谷氨酰胺环转移酶并与他们的临床疾病相关。这项研究涉及的方法将包括高压液体色谱法、放射免疫分析法、抗血清生成、氨基酸分析、质谱、免疫亲和色谱、凝胶色谱法、快速蛋白液相色谱法、等电聚焦、薄层色谱、固相和液体蛋白质合成化学。