Role of Brain Specific Tyrosne Phosphatase STEP in Neuroprotection and Death

描述(由申请人提供)：富含大脑的酪氨酸磷酸酶步骤正在成为调节与兴奋性毒性相关的神经障碍的新靶点，包括中风。STEP在大脑皮层、海马区和纹状体的神经元中表达，并参与兴奋性损伤后神经细胞的存活。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的快速激活可以对缺血损伤起到初步的神经保护作用。然而，我们发现，随着时间的推移，活性步骤的降解允许激活导致缺血性脑损伤的有害的缺血级联反应。静脉注射稳定的STEP衍生多肽(TAT-STEP-myc多肽)恢复STEP信号，可在24小时内提供对缺血性脑损伤的显著保护。我们目前研究的长期目标是确定STEP信号通路是否是治疗缺血性中风和相关神经疾病的潜在靶点。这一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，并改善幼年和老年动物的功能恢复。中心假设是，STEP信号通路，通过其在多个有害的级联缺血损伤中的协同作用，可以演变为中风治疗的独特和有效的靶点。这项拟议的研究将使用磁共振成像(MRI)和行为研究对缺血性脑损伤和神经结果进行纵向评估，并确定保护的治疗时间窗口。为了了解神经保护的分子机制(S)，这项研究将描绘出被逐步抑制的有害的级联反应。此外，本研究还将探讨与年龄相关的寡聚化增加以及随后STEP失活的机制(S)。这项研究还将评估一种耐低聚阶梯多肽在减少老龄动物缺血性损伤方面的能力。开发和使用新的、稳定的、脑渗透的和抗降解的药物，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酯在缺血性脑损伤中的神经保护潜力是创新的。我们认为，这些研究将促进我们对STEP调控的分子机制及其在年轻和老年大脑中的功能的理解。这项拟议的研究意义重大，因为它将首次提供酪氨酸磷酸酶在限制缺血性脑损伤中的作用的证据，并可能 为缺血性卒中的治疗干预提供急需的靶点。

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.