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The Role of STEP in Schizophrenia

STEP 在精神分裂症中的作用

基本信息

批准号：
8812004
负责人：
Paul J Lombroso
金额：
$ 37.46万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812004
关键词：
Acute Animal Model Antipsychotic Agents Attenuated Behavior Brain C57BL/6 Mouse Chronic Clozapine Cognition Cognitive deficits Corpus striatum structure Cyclic AMP-Dependent Protein Kinases DRD2 gene Data Disease Dopamine ErbB4 gene Exocytosis Family Functional disorder Genetic Genetic study Glutamate Receptor Glutamates Goals Hallucinogens Haloperidol Health Impaired cognition Knockout Mice Laboratories Lead Link Locomotion MAPK3 gene Mediating Membrane Membrane Proteins Memory impairment Modeling Molecular Motor Activity Mus NR1 gene NRG1 gene Neuregulins Neurons Pathway interactions Patients Persons Pharmaceutical Preparations Phencyclidine Phosphorylation Phosphorylation Site Phosphotransferases Play Prefrontal Cortex Process Protein Tyrosine Phosphatase Radial Research Role Sampling Schizophrenia Signal Pathway Signal Transduction Slice Surface Symptoms Synapses Techniques Testing Therapeutic Agents Tissues Ubiquitin Ubiquitination Water Work arm base cingulate cortex cohort density human FRAP1 protein inhibitor/antagonist mind control multicatalytic endopeptidase complex novel object recognition phosphatase inhibitor prepulse inhibition prevent receptor receptor internalization trafficking treatment effect

项目摘要

DESCRIPTION (provided by applicant): Striatal-Enriched tyrosine Phosphatase 61 (STEP61) is targeted to synaptic compartments and induces glutamate receptor internalization. We recently discovered that STEP61 is elevated in cingulate cortex of persons with schizophrenia (SZ). Our preliminary findings suggest that the increase of STEP61 results in internalization of glutamate receptors, a model consistent with the glutamate hypothesis of SZ. We also propose that the beneficial effects of antipsychotic medications are mediated through STEP61. The overall goals of this proposal are to define the mechanisms by which STEP61 mediates the loss of glutamate receptors in SZ, as well as its role in the beneficial effects of neuroleptics. In Aim 1, we will increase our samples of SZ cingulate cortex and include dorsolateral PFC. Our prediction is that STEP61 will again be elevated. We will determine the molecular mechanism by which this occurs. STEP61 is normally ubiquitinated and degraded by the proteasome. We propose that this process is disrupted in SZ. PKA phosphorylation of STEP61 is one signal that is necessary for the ubiquitination of STEP61. In the absence of PKA-phosphorylation, STEP61 is no longer ubiquitinated and degraded. We hypothesize, however, that additional kinases are required, and will identify these kinases and their phosphorylation sites in STEP61. Aim 1 will also test the hypothesis that the beneficial effects of neuroleptics are mediated through STEP61. We predict that dopamine D2R antagonists activate PKA, leading to the phosphorylation and inactivation of STEP61. Inactivation of STEP61 promotes trafficking of NMDAR to neuronal membranes. Aim 1 is significant as it explains aspects of the glutamate hypothesis of SZ as well as how neuroleptics function to ameliorate symptoms. Aim 2 will test our hypothesis in an animal model of SZ (NRG1 mice). NRG1 mice have decreased functional NMDARs on neuronal surfaces. Our hypothesis is that the loss of these receptors is mediated by activation of STEP61. We will first test our hypothesis by stimulating neuronal cultures and slices derived from WT and STEP KO mice with NRG1. Our prediction is that the absence of STEP61 will prevent NRG1-induced internalization of NMDARs. We will also test our hypothesis by crossing NRG1 with STEP KO mice. We predict that progeny null for STEP will rescue the loss of NMDARs from neuronal membranes. STEP KO mice have elevated levels of NMDARs and AMPARs on neuronal membranes. Aim 3 will test the hypothesis that these mice are less sensitive to the effects of psychotomimetic agents. Preliminary data indicate that this is the case: STEP KO mice are less sensitive to the acute effects of PCP on locomotor activity, as well as the subchronic effects of PCP on cognition. We have developed a STEP inhibitor called LDN-33960, and have shown that this compound reduces the acute effects of PCP on locomotor activity. We will test if this compound also reduces the cognitive deficits induced by PCP. Ultimately, our work has the potential of discovering a new family of therapeutic agents for SZ.

描述（由申请人提供）：纹状体富含酪氨酸磷酸酶 61 (STEP61) 靶向突触区室并诱导谷氨酸受体内化。我们最近发现精神分裂症 (SZ) 患者的扣带皮层中的 STEP61 升高。我们的初步研究结果表明，STEP61 的增加导致谷氨酸受体的内化，该模型与 SZ 的谷氨酸假说一致。我们还建议抗精神病药物的有益作用是通过 STEP61 介导的。该提案的总体目标是确定 STEP61 介导 SZ 中谷氨酸受体缺失的机制，及其在精神安定药有益作用中的作用。在目标 1 中，我们将增加 SZ 扣带皮层样本并包括背外侧 PFC。我们预测STEP61将再次提升。我们将确定发生这种情况的分子机制。 STEP61 通常被蛋白酶体泛素化和降解。我们建议在深圳扰乱这一进程。 STEP61 的 PKA 磷酸化是 STEP61 泛素化所必需的信号之一。在没有 PKA 磷酸化的情况下，STEP61 不再泛素化和降解。然而，我们假设需要额外的激酶，并将在 STEP61 中识别这些激酶及其磷酸化位点。目标 1 还将检验抗精神病药的有益作用是通过 STEP61 介导的假设。我们预测多巴胺 D2R 拮抗剂会激活 PKA，导致 STEP61 磷酸化和失活。 STEP61 失活会促进 NMDAR 转运至神经元膜。目标 1 很重要，因为它解释了 SZ 谷氨酸假说的各个方面以及精神安定药如何发挥作用来改善症状。目标 2 将在 SZ 动物模型（NRG1 小鼠）中检验我们的假设。 NRG1 小鼠神经元表面的功能性 NMDAR 减少。我们的假设是这些受体的丧失是由 STEP61 的激活介导的。我们将首先通过用 NRG1 刺激来自 WT 和 STEP KO 小鼠的神经元培养物和切片来检验我们的假设。我们的预测是，STEP61 的缺失将阻止 NRG1 诱导的 NMDAR 内化。我们还将通过将 NRG1 与 STEP KO 小鼠杂交来检验我们的假设。我们预测 STEP 无效的后代将挽救神经元膜上 NMDAR 的丢失。 STEP KO 小鼠神经元膜上的 NMDAR 和 AMPAR 水平升高。目标 3 将检验这些小鼠对拟精神病药物的作用不太敏感的假设。初步数据表明情况确实如此：STEP KO 小鼠对 PCP 对运动活动的急性影响以及 PCP 对认知的亚慢性影响不太敏感。我们开发了一种名为 LDN-33960 的 STEP 抑制剂，并表明该化合物可降低 PCP 对运动活动的急性影响。我们将测试这种化合物是否也能减少 PCP 引起的认知缺陷。最终，我们的工作有可能发现一个新的 SZ 治疗药物家族。