MONOAMINERGIC ENZYMES IN SCHIZOPHRENIA

描述：(改编自申请者摘要)酪氨酸羟基酶 (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5-羟色胺的生物合成中， 分别进行了分析。这些系统中的每一个都被牵连到 精神障碍，特别是精神分裂症。酪氨酸含量很高 --在短期内受蛋白质磷酸化的调节 从长远来看，转录控制。可选剪接(这 仅在猴子和人类中发生)产生多种TyrOH亚型 具有不同的磷酸化位点，从而使RNA剪接或 在不同亚型之间的相对mRNA/蛋白质周转率可能代表着 额外的监管水平。相比之下，尽管近距离的进化 TrpOH和TyrOH之间的功能相似之处，人们知之甚少 关于TrpOH的调节。此外，更少人知道关于 这些酶在精神障碍中的地位。 将对死后的人脑组织进行定量印迹分析 免疫标记技术。TyrOH和TrpOH蛋白水平，以及 酪氨酸异构体的相对丰度将在几个大脑中进行测定 地区。根据正在研究的大脑区域/单胺系统， 多巴脱羧酶(催化儿茶酚胺的第二步和 5-羟色胺生物合成)和多巴胺β-羟基酶(它将 多巴胺与去甲肾上腺素)的蛋白质水平也将被测定。这个 主要研究小组将：(A)自杀/猝死受害者 精神分裂症的诊断：(B)年龄匹配， 无1号轴精神障碍的猝死对照受试者。其他内容 毒理学和神经病理学筛查标准将应用于 所有病例和样本都将以盲目配对设计进行处理 进行神经化学分析。实验程序的协调 对来自同一组大脑的主要抑郁症患者的持续研究 将使两种疾病之间的直接比较成为可能。一个独立的队列 精神分裂症患者和年龄匹配的对照组(和双相情感障碍 对照组)将用于在选定的大脑中复制效果 地区。

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.