Role of brain specific tyrosine phophatase, STEP in neuroprotection and death

脑特异性酪氨酸磷酸酶 STEP 在神经保护和死亡中的作用

基本信息

批准号：
8244483
负责人：
Surojit Paul
金额：
$ 32.16万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244483
关键词：
Animal Model Attenuated Back Basal Ganglia Binding Biochemical Brain Calcium Cell Culture System Cell Death Cell Survival Cell membrane Cessation of life Cleaved cell Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Dopamine Dopamine D1 Receptor Event Extracellular Signal Regulated Kinases Glutamate Receptor Glutamates Goals HIV Hippocampus (Brain)Intervention Ischemic Brain Injury Ischemic Stroke Lesion Link MAP Kinase Signaling Pathways MAPK14 gene Mediating Methods Middle Cerebral Artery Occlusion Mitogen-Activated Protein Kinase Kinases Molecular Biology Techniques Molecular Target N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 NMDA receptor NR2B NMDA receptor Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Pathway interactions Peptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Proteolysis Regulation Research Role Serine Severities Signal Pathway Specificity Stroke Structure Testing Time Toxic effect Tyrosine abstracting attenuation cell injury excitotoxicity extracellular feeding in vivo loss of function mitogen-activated protein kinase p38 mutant nervous system disorder neuron loss neuroprotection novel novel therapeutic intervention p38 MAPK Signaling Pathway receptor research study response stress activated protein kinase therapeutic target uptake

Animal Model Attenuated Back Basal Ganglia Binding Biochemical Brain Calcium Cell Culture System Cell Death Cell Survival Cell membrane Cessation of life Cleaved cell Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Dopamine Dopamine D1 Receptor Event Extracellular Signal Regulated Kinases Glutamate Receptor Glutamates Goals HIV Hippocampus (Brain)Intervention Ischemic Brain Injury Ischemic Stroke Lesion Link MAP Kinase Signaling Pathways MAPK14 gene Mediating Methods Middle Cerebral Artery Occlusion Mitogen-Activated Protein Kinase Kinases Molecular Biology Techniques Molecular Target N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 NMDA receptor NR2B NMDA receptor Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Pathway interactions Peptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Proteolysis Regulation Research Role Serine Severities Signal Pathway Specificity Stroke Structure Testing Time Toxic effect Tyrosine abstracting attenuation cell injury excitotoxicity extracellular feeding in vivo loss of function mitogen-activated protein kinase p38 mutant nervous system disorder neuron loss neuroprotection novel novel therapeutic intervention p38 MAPK Signaling Pathway receptor research study response stress activated protein kinase therapeutic target uptake

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项目摘要

Project Summary / Abstract The long-term goal of this research is to determine the role of tyrosine phosphatases and dual-specificity phosphatases in neurological disorders of the basal ganglia and related structures. Our recent findings indicate that a striatal enriched tyrosine phosphatase, STEP, specifically expressed in the neurons of the cortex, hippocampus and striatum may participate in cell survival following an excitotoxic insult. The activity of STEP is itself regulated by the neurotransmitters dopamine and glutamate through phosphorylation and dephosphorylartion of a critical serine residue within the kinase interacting motif or KIM domain. Glutamate/NMDA receptor mediated influx of Ca2+ activates STEP, whereas dopamine/D1 receptor mediated PKA activation leads to inactivation of STEP. The proposed study will now test whether STEP is activated through NR2B-NMDA receptors, a pool of NMDA receptor that is associated with glutamate excitotoxicity. It will also investigate whether active STEP in turn can down regulate or inhibit multiple interrelated pathways that are involved in glutamate/NMDA receptor-mediated cell death. We anticipate that active STEP, as part of a feed-back loop, can down regulate NR2B-NMDA receptor channel activity through tyrosine dephosphorylation of NR2B subunit, thereby inhibiting Ca2+ overload and subsequent cell damage. It can also inhibit the activation of the p38 MAP kinase signaling pathway that has been attributed to cell death in multiple neurodegenerative disorders. In this way STEP may promote cell survival following an initial insult. However depending upon the severity of the insult STEP may be proteolytically cleaved and eventually degraded, thereby facilitating activation of cell death pathways. The study will further investigate if a constitutively active form of STEP that cannot be proteolytically cleaved and can be delivered in vivo will be able to attenuate ischemic brain damage, where the involvement of glutamate excitotoxicity is well established. These studies will involve neuron culture experiments of glutamate toxicity and an animal model of ischemic stroke and will utilize biochemical, immunocytochemical and molecular biology techniques. The findings will help us to determine whether the tyrosine phosphatase STEP may be therapeutically beneficial and can be considered for the treatment of ischemic stroke and related neurological disorders. Project Narrative The goal of the proposed study is to understand the role of a brain-enriched and neuron-specific tyrosine phosphatase, STEP, in neuronal cell death following an excitotoxic insult. The findings will help us to determine whether STEP can attenuate excitotoxic neuronal cell death and can be considered as a potential therapeutic target for the treatment of ischemic stroke and related neurological disorders.

项目摘要 /摘要这项研究的长期目标是确定酪氨酸磷酸酶和双特异性的作用基底神经节和相关结构的神经系统疾病中的磷酸酶。我们最近的发现表明该富含纹状体富集酪氨酸磷酸酶的步骤，特定于皮质神经元中兴奋性损伤后，海马和纹状体可能参与细胞存活。步骤的活动是通过磷酸化和激酶相互作用基序或KIM结构域中临界丝氨酸残基的去磷酸平原。谷氨酸/NMDA受体介导的Ca2+激活步骤的流入，而多巴胺/D1受体介导 PKA激活导致步骤失活。拟议的研究现在将测试是否激活步骤通过NR2B-NMDA受体，NR2B-NMDA受体是与谷氨酸兴奋性毒性相关的NMDA受体池。会还要研究主动步骤反过来是否可以降低或抑制多个相互关联的途径参与谷氨酸/NMDA受体介导的细胞死亡。我们预计这一积极的步骤，作为一个馈回循环，可以通过酪氨酸去磷酸化来降低NR2B-NMDA受体通道活性 NR2B亚基，从而抑制CA2+过载和随后的细胞损伤。它也可以抑制激活 p38 MAP激酶信号传导途径已归因于多个神经退行性的细胞死亡疾病。以这种方式，步骤可以促进初始侮辱后的细胞存活。但是取决于侮辱性步骤的严重程度可能会裂解并最终降解，从而促进细胞死亡途径的激活。该研究将进一步研究是否是组成型主动形式的步骤形式不能裂解蛋白水解，可以在体内递送将能够减轻缺血性脑损伤，谷氨酸兴奋性毒性的参与得出了很好的确定。这些研究将涉及神经元培养谷氨酸毒性的实验和缺血性中风的动物模型，并将利用生化，免疫细胞化学和分子生物学技术。调查结果将帮助我们确定是否酪氨酸磷酸酶步骤在治疗上可能是有益的，可以考虑缺血性中风和相关神经系统疾病。项目叙述拟议的研究的目的是了解脑增强和神经元特异性酪氨酸的作用磷酸酶，步骤，在兴奋性毒性损伤后神经元细胞死亡中。这些发现将帮助我们确定步骤是否可以减弱兴奋性神经元细胞死亡，并被视为潜在的治疗治疗缺血性中风和相关神经系统疾病的靶标。