G Protein Signaling in Brain Injury

创伤性脑损伤（TBI）是发病率和死亡率的主要原因，每年影响超过170万人 在美国长期TBI相关残疾导致患者生活质量降低， 对社会的医疗、社会和经济影响。TBI是一种异质性疾病，包括局部性和非局部性。 由氧化损伤和兴奋性毒性驱动的坏死神经元死亡区域，持续的组织炎症， 以及进行性轴索损伤和脑葡萄糖代谢低下。然而， 启动这些不同的伤害程序仍然是一个关键的知识差距，并阻碍发展， 有效的TBI治疗。值得注意的是，我们实验室的工作现在确定了神经元特异性G蛋白，RIT 2 (Rin)作为脑损伤后神经变性的调节剂。令人兴奋的初步数据表明， RIT 2 GT3沉默显著减弱了体内海马神经元死亡，减弱了海马神经元的行为功能， 功能障碍，并调节TBI后损伤激活的SARM 1 NAD酶的表达。符合 RIT 2在促进神经变性中的作用，组成性活性RIT 2的表达促进能量 崩溃和神经元死亡。此外，创新的代谢研究确定了RIT 2在调节 脑葡萄糖代谢，表明RIT 2有助于CCI后观察到的代谢功能障碍。 这些数据激发了以下中心假设：（1）RIT 2调节的信号级联有助于细胞的增殖。 脑外伤后出现神经元丢失、代谢和神经行为功能障碍，以及（2） 因此，抑制RIT 2信号传导在TBI的情况下具有广泛的治疗潜力。三 互补的目标指导我们的研究。Aim 1将评估RIT 2信号传导控制神经元的程度。 挫伤性脑损伤后的精神损失和神经功能障碍。Aim 2将采用创新的转录组学 探索RIT 2和TBI依赖的神经元基因表达改变的方法， RIT 2-SARM 1信号通路的基础，探讨RIT 2在创伤性轴索损伤中的作用。最后，研究目的 3将利用最先进的代谢方法来确定RIT 2在神经元调节中的作用。 TBI后的代谢总之，这种创新的多系统方法将产生对 脑挫伤后神经元功能障碍的分子机制，并测试治疗 靶向RIT 2及其信号传导伙伴治疗TBI的潜力。

Traumatic brain injury (TBI) is a major cause of morbidity and mortality and affects >1.7 million people annually in the United States. Long-term TBI-related disability results in reduced quality of life for the patient and prolonged medical, social, and economic effects on society. TBI is a heterogeneous disease, encompassing both localized regions of necrotic neuron death, driven by oxidative damage and excitotoxicity, persistent tissue inflammation, and both progressive axonal injury and cerebral glucose hypometabolism. However, the mechanism(s) that initiate these diverse injury programs remains a critical knowledge gap, and a barrier to the development of effective TBI treatments. Remarkably, work in our lab now identifies the neuron-specific G-protein, RIT2 (Rin), as a regulator of neurodegeneration following brain injury. Exciting preliminary data demonstrates that RIT2 GTPase silencing significantly blunts in vivo hippocampal neuron death, attenuates behavioral dysfunction, and regulates the expression of the injury-activated SARM1 NADase following TBI. In keeping with a role for RIT2 in promoting neurodegeneration, expression of constitutively active RIT2 promotes energy collapse and neuronal death. Moreover, innovative metabolic studies identify a role for RIT2 in the regulation of cerebral glucose metabolism, suggesting that RIT2 contributes to the metabolic dysfunction seen following CCI. These data motivate the central hypotheses that: (1) RIT2 regulated signaling cascades contribute to the neuronal loss, metabolic, and neurobehavioral dysfunction seen following brain trauma, and (2) that inhibition of RIT2 signaling will therefore have broad therapeutic potential in the setting of TBI. Three complementary aims guide our studies. Aim1 will evaluate the extent to which RIT2 signaling controls neuronal loss and behavorial dysfunction following contusive brain injury. Aim 2 will employee innovative transcriptomic approaches to explore RIT2- and TBI-dependent alterations in neuronal gene expression, define the molecular basis of RIT2-SARM1 signaling, and explore the role for RIT2 in traumatic axonal injury. Finally, studies in Aim 3 will leverage state-of-the-art metabolic approaches to define the role for RIT2 in the regulation of neuronal metabolism following TBI. Together, this innovative, multi-system approach will generate insights into the molecular mechanisms that orchestrate neuronal dysfunction following brain contusion, and test the therapeutic potential of targeting RIT2 and its signaling partners for the treatment of TBI.