D3 pre-mRNA processing in chronic psychosis

慢性精神病中的 D3 mRNA 前体加工

• 批准号: 6832176
• 负责人: CLAUDIA SCHMAUSS
• 金额: $ 23.63万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832176
• 关键词: RNA splicing; RNase protection assay; behavioral /social science research tag; brain mapping; clinical research; cognition; dopamine receptor; fos protein; gene expression; human tissue; immunocytochemistry; immunoprecipitation; intermolecular interaction; laboratory mouse; molecular assembly /self assembly; neurogenetics; neuropathology; neurophysiology; neuropsychology; nucleic acid structure; phospholipase C; postmortem; precursor mRNA; protein isoforms; protein structure function; schizophrenia

DESCRIPTION (provided by applicant): In brains of patients with chronic psychosis, an abnormally increased alternative splicing of dopamine D3 receptor-encoded pre-mRNA leads to a significant decrease in the expression of D3 receptor mRNA and an increased accumulation of the alternatively-spliced, truncated D3-like mRNA, named D3nf D3nf mRNA is translated into a protein that participates in heteroligomeric assemblies with full-length D3-receptor protein. In contrast to monomeric and homoligomeric D3 proteins, the D3ID30f heteroligomers do not bind ligands with high affinity. Thus, both enhanced alternative splicing of D3-pre-mRNA and the heteroligomeric assembly of D3/D3nf proteins lead to a decreased expression of functional D3 receptors. This competing renewal seeks to extend our previous postmortem study on the relative expression of D3 and D3nf mRNAs in cortical regions of a new population of schizophrenic patients and their matched controls. Further studies use in vivo RNA splicing assays in conjunction with substrate D3 pre-mRNA to test the role of phospholipase C activity in the regulation of D3- and D3nf-specific splice-site selections. Additional studies use knockout mice to study functional consequences of D3 receptor inactivation. Our studies have shown that D3 receptor inactivation leads to a decreased expression of at least two genes that modulate neuronal activity (c-fos, calbindin) in anatomic structures critically involved in those cognitive processes that are vulnerable to disruption in schizophrenia. Thus, one series of anatomic and biochemical studies aims at elucidating mechanisms that lead to a decreased D1-receptor-mediated neocortical c-fos response in mice deficient for D3 and D2 receptors. Additional behavioral studies on these mutants further test whether this decreased D1-receptor activity has consequences for their performance in cognitive tasks. A final series of immunocytochemical experiments tests whether the expression of the striatal calcium-binding protein calbindin is decreased in D3 mutants because D3 receptor expression promotes calbindin expression in ventral striatal neurons that co-express D3 receptors and calbindin or because D3-receptors play a more general role in the postnatal development of the striatal calbindin-expressing system.

描述（由申请人提供）： 在慢性精神病患者的大脑中， 多巴胺D3受体编码的前体mRNA的选择性剪接导致 D3受体mRNA表达显著降低， 选择性剪接、截短的D3样mRNA（命名为D3 nf）的积累 D3 nf mRNA被翻译成一种蛋白质， 与全长D3受体蛋白组装。与单体和 同源寡聚体D3蛋白，D3 ID 30 f异源寡聚体不结合配体， 高亲和力。因此，两者都增强了D3-前mRNA的选择性剪接， D3/D3 nf蛋白异源寡聚体组装导致 功能性D3受体这一竞争性的更新旨在扩大我们以前的 大鼠死后脑皮质D3和D3 nf mRNA相对表达的研究 新的精神分裂症患者及其匹配人群的区域 对照进一步的研究使用体内RNA剪接测定结合 底物D3前体mRNA，以测试磷脂酶C活性在细胞凋亡中的作用。 D3和D3 NF特异性剪接位点选择的调节。其他研究 使用基因敲除小鼠研究D3受体失活的功能后果。 我们的研究表明，D3受体失活会导致 至少两种调节神经元活性的基因（c-fos， 钙结合蛋白）在解剖结构中的作用， 精神分裂症中易受破坏的过程。因此，一系列 解剖学和生物化学研究的目的是阐明导致 D1-受体介导的c-fos反应在缺乏 D3和D2受体。对这些突变体的进一步行为研究 测试这种D1受体活性的降低是否会对他们的 在认知任务中的表现最后一系列的免疫细胞化学 实验测试纹状体钙结合蛋白的表达是否 蛋白质钙结合蛋白在D3突变体中减少，因为D3受体表达 促进共表达D3的腹侧纹状体神经元中的钙结合蛋白表达 受体和钙结合蛋白，或者因为D3受体在细胞内发挥更普遍的作用。 纹状体钙结合蛋白表达系统的出生后发育。