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: 8494647
• 负责人: Stephen Ashwal
• 金额: $ 30.2万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494647
• 关键词: Adolescent; Affect; Animals; Apoptosis; Apoptotic; Astrocytes; Behavioral; Brain; Brain Injuries; Calcium; Cell Survival; Cerebral Edema; Cessation of life; Child; 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; N-terminal; Neuroglia; Neurologic; Neurons; Nuclear Translocation; Outcome; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Pilot Projects; Play; Predisposition; Production; Proteins; RNA Interference; Rattus; Recovery; Regulation; Resistance; Risk; Rodent; Role; Saline; Site; Stroke; Swelling; Testing; Time; Traumatic Brain Injury; Water; angiogenesis; base; behavior test; brain repair; controlled cortical impact; disability; excitotoxicity; functional outcomes; high risk; improved; inhibitor/antagonist; interest; mortality; neurobehavioral test; neuroimaging; neuropathology; novel; pediatric traumatic brain injury; 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，经常与长期残疾和死亡的高风险相关。儿童脑外伤的独特之处在于发展为脑水肿的风险增加，这一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，在可塑性对促进内源性恢复以及对外源性药物治疗的反应至关重要的时候，发育中的大脑更容易受到兴奋毒性、细胞凋亡和炎症损伤的影响。最近的研究表明，两种新的蛋白/通路(水通道蛋白，AQPs；c-Jun N末端激酶，c-JNK)在脑缺血和创伤性损伤后的不同重叠点上发挥着关键作用。水通道蛋白是一类独特的水通道，而水通道蛋白4是脑中含量最丰富的水通道蛋白，在脑水肿的形成中起着关键作用，是开发新的减轻脑创伤后水肿药物的极佳分子候选者。AQP最近也被证明参与了有助于脑损伤和修复的其他途径。JNK通路由谷氨酸-钙激活介导，触发线粒体级联的细胞程序性死亡，加速MAPK神经元死亡，参与神经胶质细胞产生促炎介质。临床上非常感兴趣的是，在过去的两年里，已经开发出新的药物来抑制这两个途径：(I)针对AQP4的小干扰RNA(SiRNA)，siAQP4；(Ii)D-JNKI1，一种抗蛋白酶的JNK抑制肽。这项提议将检验这样一种假设，即这些新型药物可以抑制这两种蛋白质/途径，当它们结合在一起时，将在减少青少年脑外伤模型的磁共振成像、组织学和行为结果方面产生协同效应。 公共卫生相关性：创伤性脑损伤(TBI)在儿童和青少年中很常见，经常与长期残疾和死亡的高风险有关。儿童颅脑损伤的独特之处在于发生脑水肿的危险更大，以及对兴奋性毒性、细胞凋亡和炎性损伤的易感性更高。最近的研究表明，两种新的蛋白/通路(水通道蛋白，AQPs；c-Jun N末端激酶，c-JNK)在脑缺血和脑损伤后的级联反应中发挥关键作用。已经开发出新的药物来抑制这两个途径：(I)针对AQP4，siAQP4的小干扰RNA(SiRNA)；(Ii)D-JNKI1，一种抗蛋白酶的JNK抑制肽。这项提议将验证这样的假设，即这些新的药物将抑制这两种蛋白质/通路，这将在减少青少年控制的脑损伤皮质撞击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。

项目成果

Endothelial cells and astrocytes: a concerto en duo in ischemic pathophysiology.

• DOI: 10.1155/2012/176287
• 发表时间: 2012
• 期刊: International journal of cell biology
• 作者: Berezowski V;Fukuda AM;Cecchelli R;Badaut J
• 通讯作者: Badaut J

Chronic cerebrovascular dysfunction after traumatic brain injury.

• DOI: 10.1002/jnr.23732
• 发表时间: 2016-07
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Jullienne A;Obenaus A;Ichkova A;Savona-Baron C;Pearce WJ;Badaut J
• 通讯作者: Badaut J

Vasopressin V1a Receptors Regulate Cerebral Aquaporin 1 after Traumatic Brain Injury.

加压素 V1a 受体在创伤性脑损伤后调节大脑水通道蛋白 1。

• DOI: 10.1089/neu.2019.6653
• 发表时间: 2020
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: Rauen,Katrin;Pop,Viorela;Trabold,Raimund;Badaut,Jerome;Plesnila,Nikolaus
• 通讯作者: Plesnila,Nikolaus

Juvenile traumatic brain injury evolves into a chronic brain disorder: behavioral and histological changes over 6months.

• DOI: 10.1016/j.expneurol.2013.09.016
• 发表时间: 2013-12
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Kamper, Joel E.;Pop, Viorela;Fukuda, Andrew M.;Ajao, David O.;Hartman, Richard E.;Badaut, Jerome
• 通讯作者: Badaut, Jerome

Modulating the water channel AQP4 alters miRNA expression, astrocyte connectivity and water diffusion in the rodent brain.

• DOI: 10.1038/s41598-018-22268-y
• 发表时间: 2018-03-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Jullienne A;Fukuda AM;Ichkova A;Nishiyama N;Aussudre J;Obenaus A;Badaut J
• 通讯作者: Badaut J