Role of Brain Specific Tyrosne Phosphatase STEP in Neuroprotection and Death

描述（由申请人提供）：脑富集酪氨酸磷酸酶STEP正在成为调节与兴奋性毒性相关的神经系统疾病（包括中风）的新靶点。STEP在皮层、海马体和纹状体的神经元中表达，并参与兴奋性毒性损伤后神经元细胞的存活。神经递质谷氨酸在调节STEP活性中起关键作用，我们最近的研究表明，快速激活内源性STEP可以对缺血性损伤提供初步的神经保护。然而，我们发现随着时间的推移，活性STEP的降解会激活导致缺血性脑损伤的有害的缺血性级联反应。通过静脉注射稳定的STEP衍生肽（TAT-STEP-myc肽）来恢复STEP信号，可在24小时内对缺血性脑损伤提供显著保护。我们目前研究的长期目标是确定STEP信号通路是否是缺血性卒中和相关神经系统疾病治疗的潜在靶点。这项特殊应用的目的是确定恢复STEP信号的干预是否可以促进对缺血诱导的脑损伤的长期保护，并改善年轻和衰老动物的功能恢复。核心假设是，STEP信号通路通过其对缺血性损伤的多种有害级联反应的协同作用，可以演变为卒中治疗的独特而有效的靶点。该研究将利用磁共振成像（MRI）和行为学研究对缺血性脑损伤和神经预后进行纵向评估，并确定治疗保护的时间窗。为了了解神经保护的分子机制，该研究将描述由STEP抑制的有害级联反应。此外，该研究将探讨STEP寡聚化的年龄依赖性增加和随后失活的机制。该研究还将评估抗寡聚化STEP肽在减少衰老动物缺血性损伤中的能力。开发和使用新型的、稳定的、脑渗透的和抗降解的药物，以及使用STEP KO小鼠和衰老动物作为工具来确定酪氨酸磷酸酯在缺血性脑损伤中的神经保护潜力，是一种创新。我们认为这些研究将促进我们对STEP调控及其在年轻和衰老大脑中的功能的分子机制的理解。提出的研究是重要的，因为它将提供酪氨酸磷酸酶在限制缺血性脑损伤和可能的作用的第一个证据

DESCRIPTION (provided by applicant): The brain-enriched tyrosine phosphatase STEP is emerging as a novel target for modulating neurological disorders related to excitotoxicity, including stroke. STEP is expressed in neurons of the cortex, hippocampus, and striatum, and participates in neuronal cell survival following an excitotoxic insult. The neurotransmitter glutamate plays a critical role in regulating the activity of STEP and our recent studies indicate that rapid activation of endogenous STEP can provide initial neuroprotection against ischemic injury. However we found that degradation of the active STEP over time allows activation of deleterious ischemic cascades responsible for ischemic brain injury. Restoration of STEP signaling with intravenous administration of a stable STEP derived peptide (TAT-STEP-myc peptide) provides significant protection against ischemic brain injury measured at 24 hr. The long-term goal of our current research is to determine whether the STEP signaling pathway is a potential target for treatment of ischemic stroke and related neurological disorders. The objective of this particular application is to determine whether interventions to restore STEP signaling can facilitate long- term protection from ischemia-induced brain damage and improve functional recovery in both young and aging animals. The central hypothesis is that the STEP signaling pathway, through its concerted action on multiple deleterious cascades of ischemic injury can evolve as a unique and effective target for stroke therapy. The proposed study will use magnetic resonance imaging (MRI) and behavioral studies for longitudinal evaluation of ischemic brain injury and neurological outcome, and determine the therapeutic time window of protection. To understand the molecular mechanism(s) of neuroprotection, the study will delineate the deleterious cascades that are suppressed by STEP. Furthermore the study will investigate the mechanism(s) involved in age-dependent increase in oligomerization and subsequent inactivation of STEP. The study will also evaluate the ability of an oligomerization-resistant STEP peptide in reducing ischemic injury in aging animals. The development and use of novel, stable, brain-permeable and degradation-resistant agent as well as the use of STEP KO mice and aging animals as tools to establish the neuroprotective potential of a tyrosine phosphates in ischemic brain injury is innovative. We rationalize that these studies will advance our understanding of the molecular mechanisms involved in the regulation of STEP and its function in both young and aging brain. The proposed research is significant since it will provide the first evidence for the role of a tyrosine phosphatase in limiting ischemic brain injury and may provide a much-needed target for therapeutic intervention in ischemic stroke.