RIT1-mediated Protection following Traumatic Brain Injury

创伤性脑损伤（TBI）是美国死亡和永久残疾的主要原因， 每年超过170万人。TBI不仅导致组织损伤和细胞死亡， 干扰存活的神经元功能，导致神经连接改变，异常可塑性， 网络功能障碍由于TBI后功能障碍的固有多样性，迫切需要治疗TBI后功能障碍。 针对多种损伤机制的干预措施。这种多管齐下的治疗方法的发展 可能会带来巨大的临床、社会和经济效益。然而，实施这一战略需要 鉴定能够调节多种保护性/恢复性的内源性分子级联 途径。发现Rit GT3（RIT 1）在皮层神经元损伤后显著下调， 挫伤（CCI）促使研究探索Rit定向信号传导对功能性损伤的贡献。 TBI后的恢复利用RIT 1转基因小鼠的集合，令人兴奋的初步数据 证明Rit激活可减少体内神经变性并减轻认知功能障碍 在CCI之后。其他数据表明，Rit对TBI后神经发生至关重要，并促进突触 通过减少挫伤后突触丢失来保持完整性。总的来说，这些数据是第一个证明 Rit在指导TBI后神经保护和神经可塑性方面具有重要作用，并表明Rit 作为CCI后多种损伤反应机制的关键调节剂发挥作用。总体假设 是：（1）Rit在脑创伤细胞和功能恢复中起关键作用，和（2）Rit的激活 因此，Rit信号传导在TBI背景下具有广泛的治疗潜力。三个互补的目标指南 我们的研究目的1将检验挫伤依赖性Rit丢失破坏基因表达的假设 促进神经存活和神经发生的项目。在目标2中，我们将评估Rit 信号转导控制脑挫伤后神经元的存活。Rit靶向治疗的疗效将是 使用诱导型敲入小鼠模型进行评估，以允许Rit在临床相关时期内激活 在脑损伤发作后数小时至数天。目的3将检验Rit信号传导保留突触的假设。 使用转基因小鼠，电生理学和生化测定，研究创伤性脑损伤后的功能。 总的来说，这些研究有望将Rit确定为脑损伤背景下的关键信号整合中心 - 协调调节神经元存活，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.