Neuronal IL-1R1 Signaling in Mild Closed Head Injury

轻度闭合性头部损伤中的神经元 IL-1R1 信号转导

• 批准号: 10518172
• 负责人: ADAM D BACHSTETTER
• 金额: $ 44.24万
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518172
• 关键词: Acute; Address; Age; Animal Disease Models; Anti-Inflammatory Agents; Attention; Autoimmune Diseases; Axon; Behavior; Behavioral Assay; Brain; Cells; Chronic; Closed head injuries; Complex; Data; Development; Electrophysiology (science); Exhibits; FDA approved; Formulation; Functional disorder; Gene Expression Profile; Genes; Goals; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin Suppression; Interleukin-1; Interleukin-1 Receptors; Intervention; Knockout Mice; Knowledge; LoxP-flanked allele; Maintenance; Mediating; Memory; Modeling; Mus; Nature; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurons; Pathway interactions; Peripheral; Phase; Phenotype; Physiology; Process; Receptor Signaling; Recovery; RiboTag; Role; Signal Transduction; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Tissues; Traumatic Brain Injury; cell type; cognitive function; cognitive recovery; cytokine; experimental study; genetic approach; inflammatory milieu; interleukin-1 receptor accessory protein; knock-down; mouse model; nerve injury; nervous system disorder; neuroinflammation; neuroregulation; novel; preservation; response; synaptic function

ABSTRACT The cytokine interleukin-1 (IL-1) is well known to mediate detrimental inflammatory processes in peripheral tissues. IL-1 is elevated in age and in neurodegenerative disease. As a result, IL-1 has become a major focus of anti-inflammatory strategies to treat neuroinflammation following acute injury and in chronic neurodegenerative disease. Surprisingly, there is scant evidence that neurons are damaged through the direct actions of IL-1. To the contrary, a neuron-specific “non-canonical” IL-1 receptor (IL-1R1) pathway that promotes, rather than erodes, neuronal viability has been identified. Despite this paradigm-shifting observation, the non-canonical pathway has received little attention. Much remains unknown about how neuronal IL-1R1 signaling contributes to the brain's inflammatory milieu, synaptic physiology, and cognitive function, and recover from injury and progression of neurodegeneration. This knowledge gap could undermine potential neuroprotective approaches that target suppression of IL-1 as part of the mechanism-of-action. To address this knowledge gap, we will use novel mouse models exhibiting neuron-specific modulation of IL-1 signaling (i.e., IL-1R1-floxed mice to look at neuron-specific knockdown and IL-1R1-restore mice to look at the neuron-specific expression of IL-1R1). Our overarching hypothesis is that neuronal IL-1R1 signaling is inherently protective. We will test this hypothesis in the following Specific Aims: SA1 Define the role of the neuronal IL-1R1 pathway in the inflammatory response to a CHI in mice. SA2 Define the neuronal IL-1R1 pathway in homeostatic synaptic plasticity after a CHI in mice. SA3 Determine the temporal role of neuronal IL-1R1 in the cognitive recovery following a CHI. If our hypothesis is affirmed, we will provide knowledge of a new neuroprotective approach and enable the development of new formulations of existing anti-inflammatory interventions that preserve the neuroprotective functions of IL-1. The development of novel IL-1R1 therapies would include agents that only suppress the inflammatory IL-1R1 pathway or only activate the neuroprotective IL-1R1 pathway.

摘要 众所周知，细胞因子白介素1(IL-1)在外周组织中介导有害的炎症过程 纸巾。IL-1在年龄和神经退行性疾病中升高。因此，IL-1成为人们关注的主要焦点 抗炎策略治疗急性和慢性损伤后的神经炎症 神经退行性疾病。令人惊讶的是，几乎没有证据表明神经元通过直接的 IL-1的作用。相反，神经元特异性的非规范的IL-1受体(IL-1R1)途径 促进而不是侵蚀神经元的活性已经被确定。尽管有这种范式转换的观察， 非正则途径几乎没有受到关注。关于神经元IL-1R1如何 信号有助于大脑的炎症环境、突触生理和认知功能，以及 从损伤中恢复和神经退变的进展。这种知识鸿沟可能会削弱潜力。 以抑制IL-1为目标的神经保护方法是作用机制的一部分。 为了解决这一知识鸿沟，我们将使用显示神经元特异性调节IL-1的新型小鼠模型 信号(即，IL-1R1诱导的小鼠查看神经元特异性基因敲除，而IL-1R1恢复的小鼠查看 神经元特异性表达IL-1R1)。我们的主要假设是神经元IL-1R1信号是 与生俱来的保护性。 我们将在以下具体目标中检验这一假设： SA1定义了神经元IL-1R1通路在小鼠对CHI的炎症反应中的作用。 SA2在小鼠CHI后的稳态突触可塑性中定义了神经元IL-1R1通路。 SA3决定了神经元IL-1R1在脑缺血后认知恢复中的时间作用。 如果我们的假设得到证实，我们将提供一种新的神经保护方法的知识，并使 开发现有抗炎干预措施的新配方，以保护神经保护 IL-1的功能。新的IL-1R1疗法的开发将包括仅抑制 炎症性IL-1R1途径或仅激活神经保护性IL-1R1途径。