Postmortem Analysis of Dopamine Receptor-Interacting Proteins in Cortical & Subco

皮质中多巴胺受体相互作用蛋白的尸检分析

• 批准号: 6892759
• 负责人: LYNN D SELEMON
• 金额: $ 23.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-12 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892759
• 关键词: Macaca mulatta; brain mapping; calcium binding protein; calcium flux; clinical research; disease /disorder etiology; dopamine; dopamine receptor; genetic transcription; human tissue; inositol phosphates; intracellular transport; nerve /myelin protein; neurogenetics; polymerase chain reaction; protein localization; protein protein interaction; protein structure function; schizophrenia; western blottings

The dopamine hypothesis remains a prominent influence on research into the pathophysiology of schizophrenia (SCHIZ), yet the presence of consistent SCHIZ-linked abnormalities either in the presynaptic components of the dopamine system or in dopamine receptors (DRs) still remains a matter of debate. The present proposal focuses on a recently recognized group of DR-interacting proteins (DRIPs) as possible novel sites of dysfunction in SCHIZ. In pursuing this hypothesis, we have already demonstrated that the dorsolateral prefrontal cortex from SCHIZ cases of the Stanley Foundation Neuropathology Consortium express significantly increased levels of the D 1 DRIP, calcyon, and the D2 DRIP, NCS-1. These findings support our proposition that SCHIZ is associated with altered levels of specific DRIPs. It is also interesting that these two proteins strongly associate with Ca2+ signaling. Therefore, they have joined the growing list of molecules involved in Ca2+ signaling and whose abnormalities have been reported in SCHIZ. Consequently, our data uphold the central hypothesis of our Center that SCHIZ, while may be induced by multifactorial causes, is, at its core, a disease of Ca2+ signaling. The main goal of this project is to confirm and expand our examinations of DRIPs in SCHIZ, which is essential for proving both the specific hypothesis of this project and the general hypothesis of the entire Center. This will be achieved in the following specific aims: 1. We will determine whether in SCHIZ patients levels of calcyon and NCS-1 are affected in areas other than the previously-examined dorsolateral prefrontal cortex. We will also examine whether the changes in these DRIPs could be consistently observed in samples from several brain collections. 2. We will determine whether detected changes in levels of calcyon and NCS-1 proteins are associated with increased transcription of these DRIPs by regional cells. 3. We will analyze possible SCHIZ-linked changes in the proportion of calcyon- and NCS-1-containing neurons and glia among the cells of specific brain regions and their structural subdivisions. 4. We will conduct a detailed examination of the cellular and subcellular distributions of calcyon and NCS-1 in specific regions of the primate brain. 5. We will continue to evaluate additional novel DRIPs.

多巴胺假说仍然对研究的研究 精神分裂症（精神分裂症），但是在多巴胺系统的突触前成分或多巴胺受体（DRS）中存在一致的分数链接异常仍然是一个争议的问题。本提案的重点是最近公认的一组DR相互作用蛋白（滴水）作为Schiz功能障碍的新型部位。在提出这一假设时，我们已经证明了斯坦利基金会神经病理联盟的奇数病例的背外侧前额叶皮层显着提高了D 1 Drip，Colcyon和D2 Drip，NCS-1的水平。这些发现支持我们 sechiz与特定滴水水平改变有关的命题。有趣的是，这两种蛋白质与Ca2+信号传导紧密相关。因此，他们加入了涉及Ca2+信号传导的分子的日益增长的清单，并在Schiz中报道了其异常。因此，我们的数据坚持了我们中心的中心假设，即奇齐斯虽然可能是由多因素原因引起的，但其核心是CA2+信号传导的疾病。该项目的主要目标是确认和扩展我们在Schiz中滴水的检查，这对于证明该项目的具体假设和一般性的至关重要 整个中心的假设。这将在以下具体目的中实现：1。我们将确定在concyon和NCS-1的Schiz患者水平中是否在以前面临的背外侧前额叶皮层以外的地区受到影响。我们还将检查这些滴水中的变化是否可以在几个大脑收集的样品中始终如一地观察到。 2。我们将确定检测到的结石和NCS-1蛋白水平的变化是否与区域细胞对这些滴水的转录增加有关。 3。我们将分析特定大脑区域的细胞及其结构细分的细胞中含石和NCS-1的神经元和神经胶质的比例的可能分数相关的变化。 4。我们将对灵长类动物大脑的特定区域中钙和NCS-1的细胞和亚细胞分布进行详细检查。 5。我们将继续评估其他新型滴水。