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Role of Brain Specific Tyrosne Phosphatase 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：
10610467
负责人：
Surojit Paul
金额：
$ 50.34万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
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 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10610467
关键词：
Acute Animal Model Anti-Inflammatory Agents Attenuated Behavioral Brain Brain Injuries CX3CL1 gene Cause of Death Central Nervous System Diseases Cerebral Ischemia Cessation of life Chronic Clinical Communication Corpus striatum structure Development Dimerization Dopamine Dose Evaluation Failure Glutamate Receptor Glutamates Hippocampus Hypertension In Vitro Inbred SHR Rats Infiltration Inflammation Inflammatory Inflammatory Response Intervention Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Knowledge Leucocytic infiltrate Leukocytes Magnetic Resonance Imaging Middle Cerebral Artery Occlusion Mission Mus N-Methylaspartate Neuroimmune Neuronal Injury Neurons Neurotransmitters Oxidative Stress Pathogenesis Pathway interactions Peptides Peripheral Permeability Phosphoric Monoester Hydrolases Population Protein Tyrosine Phosphatase Proteins Public Health Rationalization Rattus Receptor Activation Regulation Research Resistance Role Signal Pathway Signal Transduction Stroke Testing Therapeutic Therapeutic Agents Time Transgenic Mice Up-Regulation behavior test behavioral study chemokine comorbidity disability effective therapy efficacy evaluation excitotoxicity experimental study hypertensive hypoperfusion imaging study in vitro Model in vivo innovation loss of function mortality nervous system disorder neuroinflammation neuroprotection neurotoxic novel novel therapeutics overexpression preclinical study restoration stroke intervention stroke model stroke outcome stroke patient stroke therapy therapeutic target tool

项目摘要

The brain-enriched and neuron-specific tyrosine phosphatase STEP is emerging as a novel target for modulating neurological disorders related to excitotoxicity. STEP is expressed in the cortex, striatum and hippocampus, and the activity of STEP is regulated by the neurotransmitters dopamine and glutamate. Using in vitro models of ischemia and an animal model of acute ischemic stroke we have shown that availability of active STEP is a key determinant of the extent of neuronal injury and ischemic brain damage. Our preliminary findings provide compelling evidence that oxidative stress associated with hypertension, the most prevalent comorbid condition in stroke patients, leads to significant loss of function of endogenous STEP. We also found that ischemic insult in hypertensive rats is associated with an increase in the level of a neuron-specific chemokine, CX3CL1 and exacerbation of brain injury. The objective of this proposal is to elucidate the mechanism(s) underlying the release of soluble CX3CL1 and its effect on stroke outcome under hypertensive condition. Our central hypothesis is that the cleavage and release of CX3CL1 is regulated by STEP, and loss of STEP function under hypertensive condition leads to excessive release of CX3CL1 following an ischemic insult resulting in augmentation of inflammatory responses through infiltration and activation of peripheral leukocytes. The proposed study will use wild-type and STEP knockout mice to delineate the mechanism of regulation of CX3CL1 by STEP. To evaluate the role of CX3CL1 in enhancing post-ischemic inflammatory respnse, we will utilize STEP KO mice, CX3CL1 KO mice as well soluble CX3CL1 overexpressing transgenic mice in the presence or absence of endogenous CX3CL1. Furthermore the study will delineate the mechanisms underlying the loss of STEP function under hypertensive condition and its implication for post- ischemic inflammation involving CX3CL1. Magnetic resonance imaging (MRI) and behavioral studies will be used for longitudinal evaluation of the extent of ischemic brain injury and behavioral deficits under hypertensive condition, and determine the efficacy, therapeutic time window and optimal dose of a STEP-derived peptide (TAT-STEP-myc) to confer neuroprotection. The use of STEP and CX3CL1 KO mice as well as CX3CL1 overexpressing transgenic mice, hypertensive rats and a brain-permeable and degradation-resistant STEP- derived peptide as tools to establish the role of STEP as a modulator of post-ischemic inflammatory response is innovative. We rationalize that understanding the role of STEP in limiting post-ischemic inflammatory response will help in the development of novel interventions for stroke therapy under comorbid conditions. The proposed research is significant since it will provide the first evidence for the role of a tyrosine phosphatase in neuroimmune communication and could have far reaching consequences for neurological disorders associated with oxidative stress and inflammation.

富含大脑和神经元特异性的酪氨酸磷酸酶步骤正在成为一个新的靶点调节与兴奋性毒性相关的神经功能障碍。STEP在大脑皮层、纹状体和 STEP的活性受神经递质多巴胺和谷氨酸的调节。vbl.使用在体外的缺血模型和急性缺血性中风的动物模型中，我们已经证明了活性步骤是神经元损伤和缺血性脑损伤程度的关键决定因素。我们的预赛这些发现提供了令人信服的证据，证明氧化应激与高血压有关，高血压是最普遍的卒中患者的并存状态，导致内源性台阶功能的显著丧失。我们还发现高血压大鼠的这种缺血性损伤与神经元特异性蛋白水平的增加有关趋化因子、CX3CL1与脑损伤加重这项建议的目的是澄清高血压时可溶性CX3CL1释放及其对卒中预后影响的机制(S) 条件。我们的中心假设是CX3CL1的切割和释放是由步进和丢失调节的高血压状态下阶梯功能障碍导致脑缺血后CX3CL1过度释放通过外周浸润和激活导致炎症反应增强的侮辱白细胞。这项拟议的研究将使用野生型和步进式基因敲除小鼠来描述 CX3CL1的分步调控。CX3CL1在促进脑缺血后炎症反应中的作用因此，我们将利用Step KO小鼠、CX3CL1 KO小鼠以及可溶性CX3CL1过表达转基因小鼠存在或不存在内源性CX3CL1的小鼠。此外，这项研究将勾勒出高血压状态下台阶功能丧失的机制及其在高血压后的意义涉及CX3CL1的缺血性炎症。磁共振成像(MRI)和行为研究将是用于高血压时缺血性脑损伤程度和行为障碍的纵向评估条件，并确定疗效、治疗时间窗口和最佳剂量的阶梯衍生肽 (tat-Step-myc)来提供神经保护。STEP、CX3CL1 KO小鼠及CX3CL1小鼠的应用过度表达转基因小鼠、高血压大鼠和一种脑渗透和抗降解步骤- 以衍生多肽为工具建立STEP作为缺血后炎症反应调节剂的作用是创新的。我们合理地理解了STEP在限制缺血后炎症反应中的作用 RESPONSE将有助于在共病条件下开发中风治疗的新干预措施。这个拟议中的研究意义重大，因为它将首次提供酪氨酸磷酸酶在神经免疫通讯，并可能对相关的神经疾病产生深远的后果与氧化应激和炎症有关。