MONOAMINERGIC ENZYMES IN SCHIZOPHRENIA

精神分裂症中的单胺能酶

• 批准号: 2416150
• 负责人: JOHN W HAYCOCK
• 金额: $ 8.4万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2416150
• 关键词: amine oxidase (flavin); aromatic L aminoacid decarboxylase; brain mapping; cerebral cortex; corpus striatum; dopamine beta monooxygenase; human tissue; locus coeruleus; neurochemistry; nucleus accumbens; postmortem; protein isoforms; schizophrenia; tryptophan 5 monooxygenase; tyrosine 3 monooxygenase; western blottings

DESCRIPTION: (Adapted from applicant's abstract) Tyrosine hydroxylase (TyrOH) and tryptophan hydroxylase (TrpOH) catalyze the rate-limiting steps in catecholamine (dopamine and norepinephrine) and serotonin biosynthesis, respectively. Alterations in each of these systems have been implicated in mental disorders and, in particular schizophrenia. TyrOH is highly regulated--by protein phosphorylation in the short-term and by transcriptional control in the long-term. Alternative splicing (which occurs exclusively in monkeys and humans) produces multiple TyrOH isoforms having different phosphorylation sites, such that changes in RNA splicing or in relative mRNA/protein turnover rates among isoforms could represent an additional level of regulation. By contrast, despite the close evolutionary and functional similarities between TrpOH and TyrOH, very little is known about the regulation of TrpOH. Moreover, even less is known regarding the status of these enzymes in mental disorders. Postmortem human brain tissue will be analyzed using quantitative blot immunolabeling techniques. TyrOH and TrpOH protein levels, as well as the relative abundances of TyrOH isoforms, will be determined in several brain regions. Depending upon the brain region/monoamine system being studied, DOPA decarboxylase (which catalyzes the second step in catecholamine and serotonin biosynthesis) and dopamine beta-hydroxylase (which converts dopamine to norepinephrine) protein levels will also be determined. The primary study groups will be (a) suicide/sudden death victims having diagnoses of schizophrenia from psychiatric autopsy and (b) age-matched, sudden-death control subjects having no axis 1 mental disorder. Additional toxicological and neuropathological screening criteria will be applied to all cases, and samples will be processed in a blind, matched-pairs design for the neurochemical analyses. Coordination of experimental procedures with ongoing studies of major depressives from the same collection of brains will enable direct comparisons between the disorders. An independent cohort of schizophrenics and age-matched controls (and bipolar affective disorder comparison group) will be used for replicating effects in selected brain regions.

描述：（改编自申请人摘要）酪氨酸羟化酶 （TyrOH）和色氨酸羟化酶（TrpOH）催化限速步骤 在儿茶酚胺（多巴胺和去甲肾上腺素）和血清素生物合成中， 分别 这些系统中的每一个都涉及到 精神障碍，特别是精神分裂症。 TyrOH是高度 在短期内受到蛋白质磷酸化的调节， 长期的转录控制。 选择性剪接（ 仅在猴子和人类中发生）产生多种TyrOH同种型 具有不同的磷酸化位点，使得RNA剪接或 异构体之间的相对mRNA/蛋白质周转率可能代表了 更高层次的监管。 相比之下，尽管进化过程中 TrpOH和TyrOH之间的功能相似性，知之甚少 关于TrpOH的调节。 此外，关于这一点所知甚少。 这些酶在精神障碍中的地位。 死后人脑组织将使用定量印迹分析 免疫标记技术。 TyrOH和TrpOH蛋白水平，以及 TyrOH同种型的相对丰度，将在几个脑中测定 地区 根据所研究的脑区/单胺系统， 多巴脱羧酶（其催化儿茶酚胺的第二步， 5-羟色胺生物合成）和多巴胺β-羟化酶（其将 多巴胺到去甲肾上腺素）蛋白质水平。 的 主要研究组将是（a）自杀/猝死受害者， 精神病尸检的精神分裂症诊断和（B）年龄匹配， 猝死对照组无轴1精神障碍。 额外 毒理学和神经病理学筛选标准将适用于 所有病例和样本将采用盲态配对设计进行处理 进行神经化学分析 实验程序的协调 与正在进行的对同一批大脑中的重度抑郁症患者的研究 可以直接比较不同的疾病 一个独立的队列 精神分裂症患者和年龄匹配的对照组（以及双相情感障碍） 对照组）将用于在所选脑中复制效应 地区