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（TBI）是发病率和死亡率的主要原因，每年受到170万人的影响 在美国。长期与TBI相关的残疾导致患者的生活质量降低并延长 医疗，社会和经济对社会的影响。 TBI是一种异质性疾病，包括两个局部 坏死神经元死亡区域，由氧化损伤和兴奋性毒性，持续组织炎症驱动， 以及进行性轴突损伤和脑葡萄糖低代谢。但是，机制 启动这些多样化的伤害计划仍然是一个关键的知识差距，并且是发展的障碍 有效的TBI治疗。值得注意的是，我们的实验室工作现在确定神经元特异性的G蛋白RIT2 （RIN），作为脑损伤后神经变性的调节剂。令人兴奋的初步数据证明了 RIT2 GTPase沉默在体内海马神经元死亡中显着钝化，减轻了行为 功能障碍，并调节TBI后损伤激活的SARM1 NADase的表达。符合 RIT2在促进神经变性中的作用，组成性活性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在调节中的作用 脑葡萄糖代谢，表明RIT2有助于CCI后看到的代谢功能障碍。 这些数据激发了中心假设：（1）RIT2调节的信号级联反应有助于 神经元丧失，代谢和神经行为功能障碍在脑创伤后观察到，（2） 因此，RIT2信号的抑制作用将在TBI的环境中具有广泛的治疗潜力。三 补充目标指导我们的研究。 AIM1将评估RIT2信号控制神经元的程度 造成脑损伤后的丧失和遗嘱功能障碍。 AIM 2将员工创新的转录组 探索神经元基因表达中RIT2-和TBI依赖性改变的方法，定义了分子 RIT2-SARM1信号的基础，并探索RIT2在创伤性轴突损伤中的作用。最后，在目标中进行研究 3将利用最新的代谢方法来定义RIT2在神经元调节中的作用 TBI之后的代谢。这种创新的多系统方法一起将产生对 脑挫伤后精心策划神经元功能障碍的分子机制，并测试治疗 靶向RIT2及其信号伴侣用于治疗TBI的潜力。