AQP4 and JNK Inhibition Together Reduce Edema and Excitotoxic Injury in jTBI

AQP4 和 JNK 抑制共同减少 jTBI 中的水肿和兴奋性毒性损伤

• 批准号: 7878704
• 负责人: Jerome Badaut
• 金额: $ 36.39万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878704
• 关键词: Adolescent; Affect; Animals; Apoptosis; Apoptotic; Astrocytes; Behavioral; Brain; Brain Injuries; Calcium; Cell Survival; Cerebral Edema; Cessation of life; Child; Childhood; Cicatrix; Clinical; Complex; Data; Death Domain; Dependence; Development; Dose; Edema; Event; Glutamates; Histology; Immunohistochemistry; Individual; Inflammatory; Injection of therapeutic agent; Injury; Ischemia; Lesion; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Microglia; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Neuroglia; Neurologic; Neurons; Nuclear Translocation; Outcome; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Pilot Projects; Play; Predisposition; Production; Proteins; RNA Interference; Rattus; Recovery; Regulation; Resistance; Risk; Rodent; Role; Saline; Site; Small RNA; Stroke; Swelling; Testing; Time; Traumatic Brain Injury; Water; angiogenesis; base; behavior test; controlled cortical impact; disability; excitotoxicity; functional outcomes; high risk; improved; inhibitor/antagonist; injury and repair; interest; mortality; neurobehavioral test; neuroimaging; neuropathology; novel; public health relevance; pup; response; response to injury; stress-activated protein kinase 1; therapeutic effectiveness; water channel; young adult

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is common in adolescents and young adults and is frequently associated with a high risk for long-term disability and mortality. Unique to pediatric TBI is the increased danger of developing cerebral edema, a phenomenon thought to be related to higher brain water content in the young and to developmental differences of the brain's response to injury. Likewise, the developing brain is more susceptible to excitotoxic, apoptotic and inflammatory injury at a time when plasticity is critical in promoting endogenous recovery as well as in response to exogenous pharmaceutical treatment. Recent studies have demonstrated that two novel proteins/pathways (aquaporins, AQPs; c-Jun N terminal kinase, c-JNK) play critical roles at different overlapping points in the cascade of events after ischemic and traumatic brain injury. AQPs are a unique class of water channels and AQP4, the most abundant brain AQP, plays a critical role in edema formation and constitutes an excellent molecular candidate for the development of novel agents to reduce post-TBI edema. AQPs also recently have been shown to participate in other pathways that contribute to brain injury and repair. JNK pathways, mediated by glutamate-calcium activation, trigger mitochondrial cascades of programmed cell death, accelerate MAP kinase neuronal death and participate in production of proinflammatory mediators from glial cells. Of great clinical interest is that in the last two years novel agents have been developed to inhibit these two pathways: (i) small interference RNA (siRNA) against AQP4, siAQP4; and (ii) D-JNKI1, a protease-resistant JNK-inhibiting peptide. This proposal will test the hypothesis that these novel agents can inhibit these two proteins/pathways and that when combined they will have a synergistic effect in reducing magnetic resonance imaging, histological and behavioral outcomes in a juvenile TBI model. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is common in children and adolescents and is frequently associated with a high risk of long-term disability and mortality. Unique to pediatric TBI is the greater danger of developing cerebral edema, as well as the greater susceptibility to excitotoxic, apoptotic and inflammatory injury. Recent studies have demonstrated that two novel proteins/pathways (aquaporins, AQPS; c-Jun N terminal kinase, c-JNK) play critical roles in the cascade of events after ischemia and TBI. Novel agents have been developed to inhibit these two pathways: (i) small interference RNA (siRNA) against AQP4, siAQP4; and (ii) D-JNKI1, a protease-resistant JNK-inhibiting peptide. This proposal will test the hypothesis that these novel agents will inhibit these two proteins/pathways and this will have a synergistic effect in reducing magnetic resonance imaging, histological and behavioral outcomes in a juvenile controlled cortical impact model of TBI.

描述（由申请人提供）：创伤性脑损伤（TBI）在青少年和年轻人中很常见，通常与长期残疾和死亡的高风险相关。儿童TBI的独特之处在于脑水肿的危险增加，这种现象被认为与年轻人脑含水量较高以及大脑对损伤反应的发育差异有关。同样，发育中的大脑更容易受到兴奋性毒性，凋亡和炎症损伤的时候，可塑性是至关重要的，在促进内源性恢复，以及在响应外源性药物治疗。最近的研究表明，两个新的蛋白质/途径（水通道蛋白，AQPs; c-Jun N末端激酶，c-JNK）在缺血性和创伤性脑损伤后事件级联反应的不同重叠点发挥关键作用。AQP是一类独特的水通道，AQP 4是大脑中含量最丰富的AQP，在水肿形成中发挥着关键作用，是开发减轻TBI后水肿的新型药物的优秀分子候选者。AQP最近也被证明参与其他有助于脑损伤和修复的途径。JNK途径，由谷氨酸钙激活介导，触发程序性细胞死亡的线粒体级联反应，加速MAP激酶神经元死亡，并参与从神经胶质细胞产生促炎介质。在过去的两年中，已经开发了抑制这两种途径的新型药物，这两种途径具有极大的临床意义：（i）针对AQP 4的小干扰RNA（siRNA），siAQP 4;和（ii）D-JNKI 1，一种蛋白酶抗性JNK抑制肽。该提议将检验以下假设：这些新型药剂可以抑制这两种蛋白质/通路，并且当组合时，它们将在减少幼年TBI模型中的磁共振成像、组织学和行为结果方面具有协同效应。 公共卫生关系：创伤性脑损伤（TBI）在儿童和青少年中很常见，通常与长期残疾和死亡的高风险相关。小儿TBI的独特之处在于发生脑水肿的危险性更大，以及对兴奋性毒性、凋亡和炎性损伤的易感性更大。最近的研究表明，两种新的蛋白质/途径（水通道蛋白，AQPS; c-Jun N末端激酶，c-JNK）在缺血和TBI后的事件级联中起关键作用。已经开发了新的药物来抑制这两种途径：（i）针对AQP 4的小干扰RNA（siRNA），siAQP 4;和（ii）D-JNKI 1，一种蛋白酶抗性JNK抑制肽。该提议将检验以下假设：这些新型药剂将抑制这两种蛋白质/通路，并且这将在青少年控制的TBI皮质撞击模型中在减少磁共振成像、组织学和行为结果方面具有协同效应。