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：
7466725
负责人：
Surojit Paul
金额：
$ 32.81万
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/7466725
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 Condition 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 Infarction 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 Personal Satisfaction Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Proteolysis Public Health Regulation Research Role Serine Severities Signal Pathway Specificity Stroke Structure Testing Thinking Time Toxic effect Tyrosine artery occlusion attenuation cell injury excitotoxicity extracellular feeding human MAPK14 protein in vivo loss of function mitogen-activated protein kinase p38 mutant nervous system disorder neuron loss neuroprotection novel novel therapeutics p38 MAPK Signaling Pathway 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）：本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。我们最近的研究结果表明，在皮质、海马和纹状体的神经元中特异性表达的富含纹状体的酪氨酸磷酸酶（STEP）可能参与兴奋性毒性损伤后的细胞存活。 STEP 的活性本身由神经递质多巴胺和谷氨酸通过激酶相互作用基序或 KIM 结构域内关键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+流入激活STEP，而多巴胺/D1受体介导的PKA激活导致STEP失活。拟议的研究现在将测试 STEP 是否通过 NR2B-NMDA 受体激活，NR2B-NMDA 受体是一组与谷氨酸兴奋性毒性相关的 NMDA 受体。它还将研究活性 STEP 是否可以反过来下调或抑制参与谷氨酸/NMDA 受体介导的细胞死亡的多个相互关联的途径。我们预计，活性STEP作为反馈环路的一部分，可以通过NR2B亚基的酪氨酸去磷酸化下调NR2B-NMDA受体通道活性，从而抑制Ca2+过载和随后的细胞损伤。它还可以抑制 p38 MAP 激酶信号通路的激活，该信号通路是多种神经退行性疾病中细胞死亡的原因。通过这种方式，STEP 可以促进初次损伤后的细胞存活。然而，根据损伤的严重程度，STEP 可能会被蛋白水解裂解并最终降解，从而促进细胞死亡途径的激活。该研究将进一步研究不能被蛋白水解裂解且可以在体内递送的STEP的组成型活性形式是否能够减轻缺血性脑损伤，其中谷氨酸兴奋性毒性的参与已得到充分证实。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 STEP 是否具有治疗作用，是否可以考虑用于治疗缺血性中风和相关的神经系统疾病。公共健康相关性：拟议研究的目的是了解大脑富集的神经元特异性酪氨酸磷酸酶 STEP 在兴奋性毒性损伤后神经元细胞死亡中的作用。这些发现将帮助我们确定STEP是否可以减轻兴奋毒性神经元细胞死亡，并可以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。