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正在成为调节兴奋性毒性相关神经系统疾病（包括卒中）的新靶点。STEP在皮质、海马和纹状体的神经元中表达，并参与兴奋性毒性损伤后的神经元细胞存活。神经递质谷氨酸在调节STEP活性中起着关键作用，我们最近的研究表明，内源性STEP的快速激活可以提供针对缺血损伤的初始神经保护。然而，我们发现活性STEP随时间的降解允许激活负责缺血性脑损伤的有害缺血级联。恢复STEP信号与静脉注射一个稳定的STEP衍生肽（TAT-STEP-myc肽）提供了显着的保护缺血性脑损伤测量在24 hr. The长期目标，我们目前的研究是确定是否STEP信号通路是一个潜在的目标，用于治疗缺血性中风和相关的神经系统疾病。该特定应用的目的是确定恢复STEP信号传导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老龄动物的功能恢复。中心假设是STEP信号通路通过其对缺血性损伤的多个有害级联的协同作用可以发展为中风治疗的独特且有效的靶点。拟议的研究将使用磁共振成像（MRI）和行为研究来纵向评估缺血性脑损伤和神经学结局，并确定保护的治疗时间窗。为了了解神经保护的分子机制，本研究将描述STEP抑制的有害级联反应。此外，本研究还将研究STEP寡聚化和随后失活的年龄依赖性增加所涉及的机制。该研究还将评估寡聚化抗性STEP肽在减少老龄动物缺血性损伤中的能力。开发和使用新的、稳定的、脑可渗透的和抗降解的试剂以及使用STEP KO小鼠和老龄动物作为工具来建立酪氨酸磷酸盐在缺血性脑损伤中的神经保护潜力是创新的。我们合理化，这些研究将促进我们的了解，参与STEP的调节及其在年轻和老龄化的大脑中的功能的分子机制。这项研究意义重大，因为它将首次证明酪氨酸磷酸酶在限制缺血性脑损伤中的作用， 为缺血性卒中的治疗干预提供了急需的靶点。

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.