G Protein Signaling in Brain Injury

脑损伤中的 G 蛋白信号转导

• 批准号: 10626681
• 负责人: Douglas Allen Andres
• 金额: $ 53.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626681
• 关键词: Acute; Affect; Alternative Splicing; Attenuated; Axon; Behavioral; Biochemical Pathway; Bioenergetics; Biotin; Brain; Brain Contusions; Brain Injuries; Cause of Death; Cerebrum; Clinical; Closed head injuries; Data; Development; Disease; Economics; Employee; Event; Functional disorder; GTP-Binding Proteins; Gene Expression; Genetic Transcription; Glucose; Goals; Guanosine Triphosphate Phosphohydrolases; Hippocampus (Brain); In Vitro; Inflammation; Injury; Knock-out; Knowledge; Link; Medical; Mental Depression; Metabolic; Metabolic dysfunction; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; NAD+ Nucleosidase; Necrosis; Nerve Degeneration; Nervous System Physiology; Neurologic; Neurologic Dysfunctions; Neuronal Dysfunction; Neuronal Injury; Neurons; Pathology; Pathway interactions; Patients; Persons; Positioning Attribute; Proteins; Public Health; Quality of life; RNA Splicing; Regulation; Research; RiboTag; Role; Signal Pathway; Signal Transduction; Signaling Protein; Societies; TBI treatment; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Traumatic Brain Injury; United States; Up-Regulation; Work; axon injury; controlled cortical impact; disability; economic cost; excitotoxicity; glucose metabolism; in vivo; innovation; insight; metabolic abnormality assessment; mortality; motor disorder; mouse model; neurobehavioral; neuron loss; neuronal metabolism; neuronal survival; neurotransmission; novel; novel therapeutics; oxidative damage; preservation; programs; sensor; social; stable isotope; therapeutic candidate; therapeutic evaluation; transcription factor; transcriptomics

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.

创伤性脑损伤是发病率和死亡率的主要原因，每年影响170万人。 在美国。长期的颅脑损伤相关残疾会导致患者的生活质量下降并延长 对社会的医疗、社会和经济影响。脑损伤是一种异质性疾病，既包括局限性疾病，也包括局限性疾病 由氧化损伤和兴奋性毒性、持续性组织炎症、 进行性轴索损伤和脑葡萄糖低代谢。然而，这个机制(S) 启动这些不同的伤害计划仍然是一个关键的知识差距，也是发展的障碍 有效的脑外伤治疗。值得注意的是，我们实验室的工作现在识别出神经元特异性G蛋白RIT2 (Rin)，作为脑损伤后神经退行性变的调节器。令人兴奋的初步数据显示 RIT2 GTP酶沉默显著钝化活体海马神经元死亡，减轻行为 并调节脑创伤后损伤激活的Sarm1 NADase的表达。与…保持一致 RIT2在促进神经退行性变中的作用，结构性活性RIT2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RIT2在调节 大脑葡萄糖代谢，提示RIT2参与了CCI后的代谢功能障碍。 这些数据支持以下中心假设：(1)RIT2调节的信号级联有助于 脑创伤后出现的神经元丢失、代谢和神经行为功能障碍，以及(2) 因此，抑制RIT2信号转导在脑外伤中具有广泛的治疗潜力。三 互补的目标指导着我们的研究。Aim1将评估RIT2信号控制神经元的程度 挫伤性脑损伤后的损失和行为功能障碍。目标2将员工进行创新转录 探索依赖RIT2和TBI的神经元基因表达变化的方法，定义分子 以RIT2-Sarm1信号转导为基础，探讨RIT2在创伤性轴索损伤中的作用。最后，在AIM中进行研究 3将利用最先进的代谢方法来确定RIT2在神经元调节中的作用 脑外伤后的新陈代谢。总而言之，这种创新的多系统方法将产生对 协调脑挫伤后神经元功能障碍的分子机制，并测试治疗 靶向RIT2及其信号伙伴治疗脑损伤的潜力。