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.

大脑富集的神经元特异性酪氨酸磷酸酶 STEP 正在成为治疗癌症的新靶点。调节与兴奋性毒性相关的神经系统疾病。 STEP 表达于皮质、纹状体和海马体中，STEP 的活性受神经递质多巴胺和谷氨酸的调节。使用缺血的体外模型和急性缺血性中风的动物模型我们已经证明，主动STEP是神经元损伤和缺血性脑损伤程度的关键决定因素。我们的初步研究结果提供了令人信服的证据，表明氧化应激与高血压有关，高血压是最常见的疾病中风患者的合并症会导致内源性STEP功能显着丧失。我们还发现高血压大鼠的缺血性损伤与神经元特异性水平的增加有关趋化因子、CX3CL1 和脑损伤恶化。该提案的目的是阐明可溶性CX3CL1释放的机制及其对高血压下卒中结果的影响健康）状况。我们的中心假设是 CX3CL1 的裂解和释放受 STEP 调节，并且 CX3CL1 的丢失高血压条件下STEP功能的丧失导致缺血后CX3CL1的过度释放通过渗透和激活外周炎症导致炎症反应增强白细胞。拟议的研究将使用野生型和 STEP 基因敲除小鼠来描述其机制 STEP 对 CX3CL1 的调节。评估CX3CL1在增强缺血后炎症中的作用因此，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，该研究将描绘高血压条件下STEP功能丧失的机制及其对高血压患者的影响涉及 CX3CL1 的缺血性炎症。磁共振成像（MRI）和行为研究将用于纵向评估高血压下缺血性脑损伤和行为缺陷的程度条件，并确定 STEP 衍生肽的功效、治疗时间窗和最佳剂量 (TAT-STEP-myc) 赋予神经保护作用。 STEP 和 CX3CL1 KO 小鼠以及 CX3CL1 的使用过度表达转基因小鼠、高血压大鼠和脑可渗透且抗降解的 STEP- 衍生肽作为工具来确定 STEP 作为缺血后炎症反应调节剂的作用是创新的。我们合理解释了理解 STEP 在限制缺血后炎症中的作用反应将有助于开发在共病条件下治疗中风的新干预措施。这拟议的研究意义重大，因为它将为酪氨酸磷酸酶在神经免疫通讯，可能对相关神经系统疾病产生深远的影响与氧化应激和炎症。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling.

NR2B-NMDA 受体介导的细胞内 Ca2+ 浓度增加可调节酪氨酸磷酸酶、STEP 和 ERK MAP 激酶信号传导。

DOI：
发表时间：
2010-08
期刊：
影响因子：
4.7
作者：
Paul, Surojit;Connor, John A
通讯作者：
Connor, John A

Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia.

脑部富含酪氨酸磷酸酶（STEP）在局灶性脑缺血中的神经保护作用。

DOI：
发表时间：
2013-11-06
期刊：
影响因子：
0
作者：
Deb, Ishani;Manhas, Namratta;Poddar, Ranjana;Rajagopal, Sathyanarayanan;Allan, Andrea M;Lombroso, Paul J;Rosenberg, Gary A;Candelario;Paul, Surojit
通讯作者：
Paul, Surojit

NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death.

NR2B-NMDA 受体介导的酪氨酸磷酸酶 STEP 调节谷氨酸诱导的神经元细胞死亡。