BRAIN RECEPTOR-PHOSPHATASES AND OTHER ORPHAN RECEPTORS

对孤儿等受体在中枢神经系统中功能的认识 通过使用核苷酸探针、特定的氨基酸序列和 其他方法是本项目最重要的目的。大的 功能未知的克隆受体的数量需要一个完整的 生成临床相关知识的方法。 在接下来的五年中，该项目将以(A)sigma受体为中心。 和(B)新型受体-蛋白酪氨酸磷酸酶。(A)研究I 我将研究西格玛结合下调的机制 因长期服用氟哌啶醇而产生的网站。的性质 这种抑制作用和氟哌啶醇代谢物的作用将被研究。 使用放射受体分析和随后的计算机辅助建模， 放射受体放射自显影和组织病理学检查。这些 研究对于理解 抗精神病药引起的迟发性运动障碍和其他副作用。(B)研究II 将决定受体蛋白酪氨酸磷酸酶的表达 在轴突快速萌发之前、期间和之后的mRNA水平 在发育中的大鼠大脑中的树突，并将绘制它们在 成人的大脑。定量Northern分析，原位杂交， 免疫组织化学技术将被用来确定(I) 产生特异性受体蛋白酪氨酸的细胞 磷酸酶在成年大鼠脑内的区域分布以及(Ii)是否 它们在发育和突触发生过程中会发生变化。 分子生物学技术在生物多样性研究中的应用 大脑中的受体蛋白酪氨酸磷酸酶将有助于我们的 了解它们的生理作用和可能参与的 病理过程，如阿尔茨海默病和帕金森氏症。老鼠， 老鼠和豚鼠将被用于这些研究。

The understanding of the functions of orphan and other receptors in the CNS through the use of nucleotide probes, specific amino acid sequences, and other methods is the most important purpose of this project. The large number of cloned receptors with unknown function requires an integrated approach to generate clinically relevant knowledge. During the next five years the project will center on (a) sigma receptors and (b) on the novel receptor-protein tyrosine phosphatases. (a) Study I will examine the mechanism of the down-regulation of the sigma binding sites produced by the chronic administration of haloperidol. The nature of this inhibition and the role of haloperidol metabolites will be studied using radioreceptor assays followed by computer-assisted modeling, radioreceptor autoradiography and histopathologic examinations. These studies have important implications for the understanding of neuroleptic-induced tardive dyskinesia and other side effects. (b) Study II will determine the expression of receptor-protein tyrosine phosphatases MRNA levels before, during and after the rapid sprouting of axons and dendrites in the developing rat brain, and will map their distribution in the adult brain. Quantitative Northern analysis, in situ hybridization, and immunohistochemical techniques will be used to determine (i) whether cells producing specifically characterized receptor-protein tyrosine phosphatases are regionally distributed in adult rat brain and (ii) whether they are altered during development and synaptogenesis. The application of molecular biological techniques to the investigation of receptor-protein tyrosine phosphatases in the brain will contribute to our understanding of their physiological role and putative involvement in pathological processes such as Alzheimer and Parkinson's diseases. Mice, rats and guinea pigs will be used for these studies.