RIT1-mediated Protection following Traumatic Brain Injury

RIT1 介导的脑外伤后保护

• 批准号: 10352301
• 负责人: Douglas Allen Andres
• 金额: $ 50.9万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352301
• 关键词: Acute; Affect; Area; Attenuated; Behavioral; Biochemical; Biological Assay; Brain Contusions; Brain Injuries; CREB1 gene; Cause of Death; Cell Death; Cells; Chronic; Clinical; Collection; Contusions; Cortical Contusions; Data; Development; Economics; Electrophysiology (science); Emotional; Experimental Models; Functional disorder; Gene Expression; Genetic Transcription; Guanosine Triphosphate Phosphohydrolases; Hippocampus (Brain); Hour; Impaired cognition; Individual; Injury; Knock-in Mouse; Language; Learning; Leg; Link; Mediating; Memory impairment; Modeling; Molecular; Multiple Trauma; Nerve Degeneration; Neuronal Dysfunction; Neuronal Injury; Neuronal Plasticity; Neurons; Pathway interactions; Play; Proteins; Recovery; Recovery of Function; Role; Signal Transduction; Speech; Suggestion; Survivors; Synapses; Testing; Therapeutic; Therapeutic Intervention; Thinking; Tissues; Transgenic Mice; Traumatic Brain Injury; United States; adult neurogenesis; arm; bioinformatics tool; brain repair; clinically relevant; dentate gyrus; disability; experience; experimental study; in vivo; injured; injury-related death; insight; loss of function; mouse model; network dysfunction; neurogenesis; neuron regeneration; neuronal survival; neuroprotection; preservation; programs; relating to nervous system; response to injury; social; synaptic function; targeted treatment; transcriptome sequencing; Acute; Affect; Area; Attenuated; Behavioral; Biochemical; Biological Assay; Brain Contusions; Brain Injuries; CREB1 gene; Cause of Death; Cell Death; Cells; Chronic; Clinical; Collection; Contusions; Cortical Contusions; Data; Development; Economics; Electrophysiology (science); Emotional; Experimental Models; Functional disorder; Gene Expression; Genetic Transcription; Guanosine Triphosphate Phosphohydrolases; Hippocampus (Brain); Hour; Impaired cognition; Individual; Injury; Knock-in Mouse; Language; Learning; Leg; Link; Mediating; Memory impairment; Modeling; Molecular; Multiple Trauma; Nerve Degeneration; Neuronal Dysfunction; Neuronal Injury; Neuronal Plasticity; Neurons; Pathway interactions; Play; Proteins; Recovery; Recovery of Function; Role; Signal Transduction; Speech; Suggestion; Survivors; Synapses; Testing; Therapeutic; Therapeutic Intervention; Thinking; Tissues; Transgenic Mice; Traumatic Brain Injury; United States; adult neurogenesis; arm; bioinformatics tool; brain repair; clinically relevant; dentate gyrus; disability; experience; experimental study; in vivo; injured; injury-related death; insight; loss of function; mouse model; network dysfunction; neurogenesis; neuron regeneration; neuronal survival; neuroprotection; preservation; programs; relating to nervous system; response to injury; social; synaptic function; targeted treatment; transcriptome sequencing

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.

创伤性脑损伤（TBI）是美国影响的主要原因和永久性残疾 每年超过170万人。 TBI不仅会导致组织损伤和细胞死亡，而且可以 在神经元功能中存活的驱动性，导致神经元连通性，可塑性异常和 网络功能障碍。由于TBI后功能障碍的继承多样性，对治疗存在关键需求 针对多种伤害机制的干预措施。开发这种多泛力治疗方法 可能具有巨大的临床，社会和经济利益。但是，实施此策略需要 鉴定能够调节多重保护/恢复的内源性分子级联 途径。皮质后，RIT GTPase（RIT1）的发现急剧下调 挫伤损伤（CCI）促使研究探讨了RIT指导信号对功能的贡献 TBI后的恢复。利用RIT1转基因小鼠的集合，令人兴奋的初步数据 证明RIT激活减少体内神经变性并减轻认知功能障碍 遵循CCI。其他数据表明，RIT对于TBI后神经发生至关重要，并促进突触 通过降低结合后的合成损失来完整性。这些数据集体是第一个证明 RIT在TBI后指导神经保护和神经塑性的重要作用，并表明RIT 在CCI后充当了多个损伤反应机制的关键调节剂。总体假设 是：（1）RIT在脑创伤中的细胞和功能恢复中起关键作用，（2）激活 因此，RIT信号在TBI的环境中具有广泛的治疗潜力。三个完整的目标指南 我们的研究。 AIM 1将检验以下假设：挫伤依赖性RIT损失会破坏基因表达 促进神经存在和神经发生的程序。在AIM 2中，我们将评估多大程度的程度 信号传导控制连续脑损伤后神经元存活。以RIT为目标的疗法的效率将是 使用诱导的敲入小鼠模型进行评估以允许在临床相关的时期内激活RIT 脑损伤发作后数小时。 AIM 3将测试RIT信号传导可保留突触的假设 使用转基因小鼠，电生理学和生化测定后，脑外伤后的功能。 总体而言，这些研究有望将RIT识别为脑损伤的关键信号整合中心 - 策划调节神经元存活的内源性途径，促进神经元再生， 并控制神经塑性机制。