RIT1-mediated Protection following Traumatic Brain Injury

创伤性脑损伤(TBI)是美国人死亡和永久残疾的主要原因，影响 每年超过170万人。脑外伤不仅会导致组织损伤和细胞死亡，而且可以 扰乱存活的神经元功能，导致神经连接性改变，异常可塑性，以及 网络功能障碍。由于脑外伤后功能障碍的内在多样性，迫切需要治疗。 针对多种伤害机制的干预措施。这种多管齐下的治疗方法的发展 可能会产生巨大的临床、社会效益和经济效益。然而，这一战略的实施需要 具有多种保护/修复调节功能的内源性分子级联的鉴定 小路。发现RIT GTPase(RIT1)在皮质损伤后显著下调 挫伤(CCI)促使研究探索RIT定向信号对功能的贡献 颅脑损伤后恢复。利用一组RIT1转基因小鼠，令人兴奋的初步数据 证明RIT激活可减少体内神经退行性变并缓解认知功能障碍 遵循CCI。更多的数据表明，RIT对脑损伤后的神经发生和促进突触是至关重要的 通过减少挫伤后突触丢失来保持完整性。总体而言，这些数据是第一个证明 RIT在脑外伤后神经保护和神经可塑性中的重要作用，提示RIT 作为CCI后多种损伤反应机制的关键调节因子。总体假设 即：(1)RIT在脑创伤后细胞和功能恢复中起关键作用；(2)RIT激活 因此，RIT信号在脑外伤中具有广泛的治疗潜力。三个互补的目标导向 我们的学习。目标1将验证挫伤依赖的RIT丢失扰乱基因表达的假设 促进神经存活和神经再生的项目。在目标2中，我们将评估RIT的程度 信号控制脑挫伤后神经元的存活。RIT靶向治疗的疗效将是 使用可诱导的敲入小鼠模型进行评估，以允许在临床相关的时间段内激活RIT 在脑损伤发生几小时到几天后。目标3将检验RIT信号保留突触的假设 使用转基因小鼠、电生理学和生化分析研究脑损伤后的功能。 总体而言，这些研究有望确定RIT在脑损伤的背景下是一个关键的信号整合中心。 -协调多种内源性途径，调节神经元存活，促进神经元再生， 并控制神经可塑性机制。

Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affecting more than 1.7 million individuals each year. TBI not only results in tissue damage and cell death, but can perturb surviving neuronal function, leading to alterations in neural connectivity, abnormal plasticity, and network dysfunction. Due to the inherent diversity in post-TBI dysfunction, a critical need exists for therapeutic interventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approaches could have enormous clinical, social, and economic benefit. However, implementation of this strategy requires the identification of endogenous molecular cascades capable of regulating multiple protective/restorative pathways. The discovery that the Rit GTPase (RIT1) is dramatically down-regulated following cortical contusion injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functional recovery following TBI. Drawing upon a collection of RIT1 transgenic mice, exciting preliminary data demonstrate that Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunction following CCI. Additional data suggest that Rit is critical for post-TBI neurogenesis and promotes synaptic integrity by reducing post-contusion synaptic loss. Collectively these data are the first to demonstrate a significant role for Rit in directing neuroprotection and neuroplasticity following TBI, and suggest that Rit functions as a linchpin regulator of multiple injury response mechanisms following CCI. The overall hypothesis is that: (1) Rit plays a key role in cellular and functional recovery from brain trauma, and (2) that activation of Rit signaling therefore has broad therapeutic potential in the setting of TBI. Three complementary aims guide our studies. Aim 1 will test the hypothesis that contusion-dependent Rit loss disrupts gene expression programs that promote neural survival and neurogenesis. In Aim 2 we will evaluate the extent to which Rit signaling controls neuronal survival after contusive brain injury. The efficacy of Rit-targeted therapies will be evaluated using an inducible knock-in mouse model to permit Rit activation over a clinically relevant period of hours to days after the onset of brain injury. Aim 3 will test the hypothesis that Rit signaling preserves synaptic function following traumatic brain injury using transgenic mice, electrophysiology, and biochemical assays. Overall, these studies are expected to identify Rit as a crucial signal integration hub in the setting of brain injury – orchestrating diverse endogenous pathways that regulate neuronal survival, promote neuronal regeneration, and control neuroplasticity mechanisms.