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

• 批准号: 8898472
• 负责人: Surojit Paul
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898472
• 关键词: Acute; Aging; Animals; Behavioral; Brain; Brain Injuries; Cell Survival; Cessation of life; Clinical Trials; Corpus striatum structure; Development; Evaluation; Event; Genes; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); In Vitro; Injury; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Knowledge; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Middle Cerebral Artery Occlusion; Mission; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurodegenerative Disorders; Neurologic; Neurological outcome; Neurons; Neuroprotective Agents; Neurotransmitters; Oxidative Stress; Pathway interactions; Peptides; Phosphoric Monoester Hydrolases; Play; Predisposition; Process; Protein Tyrosine Phosphatase; Proteins; Public Health; Rattus; Receptor Activation; Recovery; Recovery of Function; Regulation; Reperfusion Therapy; Research; Resistance; Role; Signal Pathway; Signal Transduction; Stroke; Synaptic plasticity; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tyrosine; Work; acute stroke; age effect; age related; aging brain; aging population; base; behavior test; clinically relevant; cytotoxic; disability; excitotoxicity; improved; in vivo; innovation; inorganic phosphate; insight; intravenous administration; mortality; nervous system disorder; neuroprotection; novel; novel therapeutics; post stroke; receptor; research study; response; restoration; stroke therapy; tool

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.

描述（由申请人提供）：富含大脑的酪氨酸磷酸酶 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神经元细胞的存活。神经递质谷氨酸在调节 STEP 的活性中起着至关重要的作用，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性损伤的初步神经保护。然而我们发现，随着时间的推移，活性STEP的降解会激活有害的缺血级联反应，从而导致缺血性脑损伤。通过静脉注射稳定的 STEP 衍生肽（TAT-STEP-myc 肽）来恢复 STEP 信号传导，可以在 24 小时测量到对缺血性脑损伤的显着保护。我们当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系统疾病的潜在靶点。这一特定应用的目的是确定恢复 STEP 信号传导的干预措施是否可以促进长期保护年轻和老年动物免受缺血引起的脑损伤并改善功能恢复。核心假设是，STEP 信号通路通过其对缺血性损伤的多个有害级联的协同作用，可以发展成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）和行为研究对缺血性脑损伤和神经系统结果进行纵向评估，并确定保护的治疗时间窗。为了了解神经保护的分子机制，该研究将描述 STEP 抑制的有害级联反应。此外，该研究还将探讨年龄依赖性寡聚化增加和随后 STEP 失活的机制。该研究还将评估抗寡聚化的 STEP 肽减少衰老动物缺血性损伤的能力。新型、稳定、脑渗透性和抗降解剂的开发和使用以及使用 STEP KO 小鼠和衰老动物作为工具来确定酪氨酸磷酸盐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增进我们对 STEP 调节的分子机制及其在年轻和衰老大脑中的功能的理解。拟议的研究意义重大，因为它将为酪氨酸磷酸酶在限制缺血性脑损伤中的作用提供第一个证据，并可能 为缺血性中风的治疗干预提供了急需的目标。