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

基本信息

批准号：
10656547
负责人：
ADAM D BACHSTETTER
金额：
$ 42.91万
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 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656547
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 inducible Cre inflammatory milieu interleukin-1 receptor accessory protein knock-down mouse model nerve injury nervous system disorder neuroinflammation neuroprotection neuroregulation novel preservation response synaptic function

项目摘要

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.

抽象的众所周知，细胞因子白细胞介素-1 (IL-1) 可介导外周炎症过程。 IL-1 在年龄和神经退行性疾病中升高，因此，IL-1 已成为主要焦点。治疗急性损伤和慢性损伤后神经炎症的抗炎策略令人惊讶的是，很少有证据表明神经元是通过直接损伤而受损的。相反，神经元特异性的“非典型”IL-1 受体 (IL-1R1) 通路尽管有这种范式转变的观察，但已确定促进而不是削弱神经活力。 IL-1R1 的神经通路如何发挥作用尚不清楚。信号传导有助于大脑的炎症环境、突触生理学和认知功能，并且从损伤中恢复和神经退行性变的进展可能会削弱潜力。以抑制 IL-1 作为作用机制的一部分的神经保护方法。为了解决这一知识差距，我们将使用表现出 IL-1 神经元特异性调节的新型小鼠模型信号传导（即，IL-1R1-floxed 小鼠观察神经元特异性敲低，IL-1R1-restore 小鼠观察神经元特异性敲除） IL-1R1 的神经元特异性表达）。我们的总体假设是神经元 IL-1R1 信号传导是本质上具有保护性。我们将在以下具体目标中检验这一假设： SA1 定义神经元 IL-1R1 通路在小鼠 CHI 炎症反应中的作用。 SA2 定义小鼠 CHI 后稳态突触可塑性中的神经元 IL-1R1 通路。 SA3 确定神经元 IL-1R1 在 CHI 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，以保留神经保护作用新型 IL-1R1 疗法的开发将包括仅抑制 IL-1 的药物。炎症性 IL-1R1 通路或仅激活神经保护性 IL-1R1 通路。