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：
7794989
负责人：
Surojit Paul
金额：
$ 32.48万
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/7794989
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 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 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 public health relevance receptor research study response stress activated protein kinase therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): 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 dephosphorylation 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：这项研究的长期目标是确定酪氨酸磷酸酶和双特异性磷酸酶在基底神经节和相关结构的神经系统疾病中的作用。我们最近的发现表明，在皮质，海马和纹状体的神经元中特别表达的纹状体富集的酪氨酸磷酸酶可能会在兴奋性毒性侮辱后参与细胞存活。步骤的活性本身受神经递质多巴胺和谷氨酸的调节，并通过激酶相互作用基序或KIM结构域内的临界丝氨酸残基的磷酸化和去磷酸化来调节。谷氨酸/NMDA受体介导的Ca2+激活步骤的流入，而多巴胺/D1受体介导的PKA激活导致步骤失活。拟议的研究现在将测试是否通过NR2B-NMDA受体激活步骤，NR2B-NMDA受体是与谷氨酸兴奋性毒性相关的NMDA受体池。它还将调查主动步骤反过来是否可以降低或抑制与谷氨酸/NMDA受体介导的细胞死亡有关的多个相互关联的途径。我们预计，作为馈回循环的一部分，主动步骤可以通过NR2B亚基的酪氨酸去磷酸化来降低NR2B-NMDA受体通道活性，从而抑制Ca2+过载，并随后的细胞损伤。它还可以抑制多种神经退行性疾病中细胞死亡的p38 MAP激酶信号通路的激活。以这种方式，步骤可以促进初始侮辱后的细胞存活。但是，根据侮辱步骤的严重程度，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不能裂解蛋白水解的组成型活跃形式，可以在体内递送，可以在体内弥补缺血性脑损伤，在这种情况下，在谷氨酸兴奋性的参与中得到很好的确定。这些研究将涉及谷氨酸毒性的神经元培养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。这些发现将帮助我们确定酪氨酸磷酸酶步骤是否可能在治疗上有益，并且可以考虑治疗缺血性中风和相关神经系统疾病。公共卫生相关性：拟议研究的目的是了解脑毒性损伤后神经元细胞死亡中脑增强和神经元特异性酪氨酸磷酸酶的作用。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，并被视为治疗缺血性中风和相关神经系统疾病的潜在治疗靶点。