G Protein Signaling in Brain Injury

脑损伤中的 G 蛋白信号转导

基本信息

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
项目类别：
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

项目摘要

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，每年影响超过 170 万人在美国。长期 TBI 相关的残疾会导致患者的生活质量下降，并延长治疗时间。对社会的医疗、社会和经济影响。 TBI 是一种异质性疾病，包括局部由氧化损伤和兴奋性毒性、持续性组织炎症驱动的坏死神经元死亡区域，以及进行性轴突损伤和脑葡萄糖代谢低下。然而，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，也是发展的障碍有效的 TBI 治疗。值得注意的是，我们实验室的工作现已鉴定出神经元特异性 G 蛋白，RIT2 (Rin)，作为脑损伤后神经退行性变的调节剂。令人兴奋的初步数据表明 RIT2 GTPase 沉默显着减弱体内海马神经元死亡，减弱行为功能障碍，并调节 TBI 后损伤激活的 SARM1 NADase 的表达。符合 RIT2 在促进神经退行性变中的作用，组成型活性 RIT2 的表达可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 在调节脑葡萄糖代谢，表明 RIT2 导致 CCI 后出现的代谢功能障碍。这些数据激发了以下中心假设：(1) RIT2 调节的信号级联有助于脑外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 信号传导在 TBI 中具有广泛的治疗潜力。三互补的目标指导我们的学习。 Aim1 将评估 RIT2 信号控制神经元的程度挫伤性脑损伤后的丧失和行为功能障碍。目标 2 将采用创新转录组学探索神经元基因表达中 RIT2 和 TBI 依赖性改变的方法，定义分子 RIT2-SARM1信号传导的基础，并探讨RIT2在创伤性轴突损伤中的作用。最后，学习Aim 3 将利用最先进的代谢方法来定义 RIT2 在神经元调节中的作用 TBI 后的新陈代谢。总之，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，并测试治疗方法靶向 RIT2 及其信号传导伴侣治疗 TBI 的潜力。