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Oxidative modification of K+ channels as a mechanism of toxicity in TBI

K 通道的氧化修饰作为 TBI 毒性机制

基本信息

批准号：
9086680
负责人：
FEDERICO SESTI
金额：
$ 19.88万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086680
关键词：
Address Affect Alder plant Apoptosis Apoptotic Behavioral Blood - brain barrier anatomy Brain Cell Death Cell membrane Collaborations DNA Dasatinib Drug Targeting Etiology FDA approved Free Radicals Genetic Goals Hippocampus (Brain)Human In Vitro Injury JNK-activating protein kinase Laboratories Lateral Lead Lesion Lipids Liquid substance Mediating Modification Molecular Mus Neurologic Neurons Operative Surgical Procedures Pathway interactions Percussion Pharmaceutical Preparations Pharmacological Treatment Play Population Potassium Potassium Channel Proteins Reactive Oxygen Species Regulation Research Resistance Role Signal Pathway Sprycel Staging System Testing Therapeutic Tissues Toxic effect Transgenic Mice Translating Traumatic Brain Injury Traumatic injury Tyrosine Kinase Inhibitor Variant Voltage-Gated Potassium Channel Work behavioral deficiency behavioral outcome disability fluid percussion injury genetic approach improved in vivo inhibitor/antagonist insight leukemia mouse model neuron loss neuronal excitability neuronal survival novel therapeutic intervention oxidation oxidative damage prevent public health relevance src-Family Kinases success

项目摘要

DESCRIPTION (provided by applicant): Following traumatic brain injury (TBI) there is copious release of oxygen radicals that damage proteins, DNA and cell membranes ultimately resulting in long-term neurological disabilities. Our laboratory has shown that K+ channels, which are key to neuronal excitability and survival, are substrates of free radicals. In particular, we showed tht oxidation of KCNB1 (formerly Kv2.1), a K+ channel abundant in brain, induces neuronal death by apoptosis via a Src tyrosine kinase mediated pathway. We have identified a FDA-approved, blood-brain barrier permeable drug that directly impinges on this apoptotic pathway. KCNB1 plays a major role in determining the intrinsic excitability of neurons of the cortex and hippocampus. This implies that-following traumatic injury-oxidized KCNB1 channels and/or the other components of the signaling pathways activated by their oxidation may contribute to loss of brain function. The broad goal of this project is to address the role of oxidation of KCNB1 channels in traumatic brain injury in vivo and in vitro. We will evaluate the mechanism by which oxidized KCNB1 channels contribute to neuronal death, their potential contribution to the tissue damage that occurs following traumatic brain injury and the therapeutic potential of a FDA-approved drug. Experimental testing will be carried out in mice, including a transgenic mouse expressing a KCNB1 variant resistant to oxidation and cultured primary neurons. As no effective pharmacological treatment exists for traumatic brain injury, our proposal to test the role of oxidation of KCNB1 represents a critical step forward in determining whether KCNB1 and other components of the signaling pathways activated by its oxidation, such as Src tyrosine kinases, represent bona fide drug targets for limiting the cellular devastation that accompanies traumatic brain injury. In addition, this research will add important insight into both the regulation and th downstream pathways impacted by the channel.

描述(申请人提供)：创伤性脑损伤(TBI)后，会释放大量的氧自由基，破坏蛋白质、DNA和细胞膜，最终导致长期的神经残疾。我们的实验室已经证明，K+通道是自由基的底物，对神经元的兴奋性和存活率至关重要。特别是，我们发现KCNB1(以前的Kv2.1)是大脑中一种丰富的K+通道，它的氧化通过Src酪氨酸激酶介导的途径诱导神经元死亡。我们已经确定了一种FDA批准的血脑屏障通透性药物，它直接影响到这一凋亡途径。KCNB1在决定大脑皮层和海马神经元的内在兴奋性方面起着重要作用。这意味着在创伤后，氧化的KCNB1通道和/或由其氧化激活的信号通路的其他成分可能导致大脑功能的丧失。这个项目的主要目标是解决KCNB1氧化的作用创伤性脑损伤的体内和体外通道。我们将评估氧化的KCNB1通道导致神经元死亡的机制，它们对创伤性脑损伤后发生的组织损伤的潜在贡献，以及FDA批准的药物的治疗潜力。实验测试将在小鼠身上进行，包括表达抗氧化性KCNB1变体的转基因小鼠和培养的原代神经元。由于创伤性脑损伤尚无有效的药物治疗方法，我们提出的测试KCNB1氧化作用的建议是在确定KCNB1及其氧化激活的信号通路的其他组成部分(如Src酪氨酸激酶)是否代表真正的药物靶点以限制伴随创伤性脑损伤的细胞破坏方面向前迈出的关键一步。此外，这项研究还将对受航道影响的调节和下游通路增加重要的洞察。