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

描述（由申请人提供）：创伤性脑损伤（TBI）常见于青少年和年轻人，通常与长期残疾和死亡的高风险相关。儿童创伤性脑损伤的独特之处在于发生脑水肿的危险增加，这一现象被认为与年轻人较高的脑含水量以及大脑对损伤反应的发育差异有关。同样，当可塑性在促进内源性恢复以及对外源性药物治疗的反应中至关重要时，发育中的大脑更容易受到兴奋性毒性、细胞凋亡和炎症性损伤的影响。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）在缺血性和创伤性脑损伤后的级联事件的不同重叠点起关键作用。AQP是一类独特的水通道，而AQP4是最丰富的脑AQP，在水肿形成中起着关键作用，是开发新型药物减少tbi后水肿的优秀分子候选者。aqp最近也被证明参与了其他有助于脑损伤和修复的途径。JNK通路由谷氨酸钙活化介导，触发线粒体级联程序性细胞死亡，加速MAP激酶神经元死亡，并参与胶质细胞促炎介质的产生。在过去的两年里，有很大的临床兴趣是开发了新的药物来抑制这两种途径：(i)小干扰RNA （siRNA）对抗AQP4， siAQP4；（ii） D-JNKI1，一种蛋白酶抗性的jnk抑制肽。这一提议将验证这一假设，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，它们将在减少青少年TBI模型的磁共振成像、组织学和行为结果方面产生协同效应。

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.