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: 8820942
• 负责人: Surojit Paul
• 金额: $ 33.03万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820942
• 关键词: Acute; Aging; Animals; 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; 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; behavioral study; 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; targeted treatment; 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）：富含脑添加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系统疾病的新目标，包括中风。步骤在皮质，海马和纹状体的神经元中表达，并在兴奋性毒性损伤后参与神经元细胞的存活。神经递质谷氨酸在调节步骤的活性中起着至关重要的作用，而我们最近的研究表明，内源性步骤的快速激活可以提供针对缺血性损伤的初始神经保护作用。但是，我们发现，随着时间的推移，主动步骤的降解允许激活导致缺血性脑损伤的有害缺血级联反应。通过静脉内施用稳定的阶梯衍生肽（TAT-Step-Myc肽）的静脉信号传导可为24小时测得的缺血性脑损伤提供明显的保护。我们当前研究的长期目标是确定步骤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目标。该特定应用的目的是确定恢复步骤信号传导的干预措施是否可以促进长期保护不受缺血引起的脑损伤并改善年轻动物和衰老动物的功能恢复。中心假设是，通过对多个有害缺血性损伤的有害级联的一致作用，步骤信号通路可以作为中风治疗的独特而有效的目标发展。拟议的研究将使用磁共振成像（MRI）和行为研究进行缺血性脑损伤和神经系统结果的纵向评估，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，该研究将描绘出逐步抑制的有害级联反应。此外，该研究将研究涉及年龄依赖性增加的寡聚化和随后的步骤失活的机制。该研究还将评估抗寡聚化的阶梯肽在减少衰老动物缺血性损伤方面的能力。新型，稳定，可渗透和降解剂的开发和使用以及使用步骤KO小鼠和老化动物作为在缺血性脑损伤中建立酪氨酸磷酸盐的神经保护潜力的工具是创新的。我们合理地认为，这些研究将提高我们对在年轻大脑和衰老大脑中涉及的分子机制及其功能所涉及的分子机制的理解。拟议的研究很重要，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，并且可能 为缺血性中风提供了急需的治疗干预靶标。