Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury

脑外伤后 IL-1/IL-1R1 信号传导的细胞特异性作用

• 批准号: 10307112
• 负责人: ADAM D BACHSTETTER
• 金额: $ 32.72万
• 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: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307112
• 关键词: Acute; Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Attenuated; Blood Vessels; Brain; Cells; Central Nervous System Diseases; Chronic; Clinical; Closed head injuries; Data; Development; Disease; Electrophysiology (science); Endothelial Cells; Endothelium; Extravasation; FDA approved; Failure; Functional disorder; Generations; Genetic; Goals; Immunomodulators; Immunosuppressive Agents; Impaired cognition; Impairment; Inflammation; Inflammatory; Injury; Interleukin Suppression; Interleukin-1; Interleukin-1 Receptors; Knockout Mice; Knowledge; Lead; Learning; LoxP-flanked allele; Memory; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Outcome; Pathologic; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Public Health; Radial; Receptor Signaling; Regulation; Residual state; Risk Factors; Role; Severities; Signal Transduction; Synapses; Synaptic plasticity; Testing; Time; Traumatic Brain Injury; Vascular Diseases; Vascular remodeling; Vertebral column; arm; blood-brain barrier permeabilization; brain endothelial cell; cell type; central nervous system injury; cerebral atrophy; density; improved; mild traumatic brain injury; mouse model; neuroinflammation; neuroprotection; novel; response; restoration; severe injury; targeted treatment; water maze

ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following a traumatic brain injury (TBI), and substantial evidence suggests therapies targeting the interleukin-1 receptor (IL-1R1) pathway may control neuroinflammation. Despite the promise, there have been limited attempts to move anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. We hold that a critical reason for the lack of progress on this promising target is the incomplete understanding of the mechanistic underpinnings of IL-1 signaling after a TBI. It is well-recognized that the clinical picture of TBI is a spectrum of different primary injury mechanisms and injury severities, and that it is necessary to understand the secondary injury mechanism as they relate to the primary injury. Over 75% of TBIs are classified as mild. While not all TBIs lead to neurodegeneration, a mild TBI can result in progressive brain atrophy and persistent cognitive dysfunction, and is a known risk factor for the development of Alzheimer’s disease and related dementias. The current knowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury. Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling, and our model of mild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge by testing the role of IL-1R1 following a mild TBI, and for the first time, define a cellular mechanism for the pathological effects of IL-1R1 following a mild TBI. Importantly our exciting preliminary data has uncovered a critical role for the brain endothelium in regulating neuroinflammation, which is dependent on IL-1R1. Our preliminary results have led us to propose the overall hypothesis: Secondary neuronal injury following a mild TBI is driven by neuroinflammation and vascular dysfunction, which can be reduced through suppression of IL-1R1. The actions of IL-1R1 following a mild TBI will require the involvement of endothelial cells. We will test our hypothesis in the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mild TBI, and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our results will fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotection after a mild TBI, and potential for other disease associated with neuroinflammation (i.e., Alzheimer’s disease).

摘要 神经炎症的管理是一个有希望的目标，以改善患者的结果后， 创伤性脑损伤（TBI），大量证据表明治疗靶向白细胞介素-1受体 （IL-1 R1）通路可能控制神经炎症。尽管有这样的承诺， 将抗白细胞介素-1（IL-1）药物用于TBI神经保护。我们认为，一个关键的原因，缺乏 在这个有希望的目标上取得进展的原因是对IL-1的机制基础的不完全理解 TBI后的信号众所周知，TBI的临床表现是一系列不同的原发性损伤 机制和损伤严重程度，并且有必要了解继发性损伤机制， 它们与原发性损伤有关。超过75%的TBI被归类为轻度。虽然不是所有的TBI都会导致 轻度TBI可导致进行性脑萎缩和持续性认知功能障碍， 是阿尔茨海默病和相关痴呆症的一个已知的危险因素。当前 TBI后IL-1 / IL-1 R1信号传导的知识几乎完全是在中度至重度损伤后。 使用我们的新的遗传小鼠模型，允许IL-1 R1信号传导的细胞类型调节，以及我们的模型， 闭合性颅脑损伤（CHI）引起的轻度TBI，我们将通过以下方式解决我们知识中的这一根本性差距： 测试IL-1 R1在轻度TBI后的作用，并首次定义了 IL-1 R1在轻度TBI后的病理作用。重要的是，我们令人兴奋的初步数据揭示了一个 脑内皮在调节神经炎症中的关键作用，这依赖于IL-1 R1。我们 初步结果使我们提出了一个总体假设：继发性神经元损伤后， 轻度TBI是由神经炎症和血管功能障碍引起的，可以通过 抑制IL-1 R1。IL-1 R1在轻度TBI后的作用将需要以下参与： 内皮细胞我们将在以下目标中检验我们的假设： 目的1：评估内皮细胞IL-1 R1信号在神经炎症前馈回路中的作用。 目的2：确定内皮细胞IL-1 R1信号在血管对CHI反应中的作用。 目的3：阐明内皮细胞IL-1 R1信号在突触可塑性和空间学习中的作用， 记忆跟随着CHI。 这些研究的成功完成将增加我们对IL-1 R1在轻度脑缺血后作用的理解。 TBI，并定义脑内皮细胞在轻度TBI的神经炎症反应中的作用。我们的结果 将填补关于如何最好地靶向神经炎症以实现神经保护的关键知识空白 在轻度TBI后，以及与神经炎症相关的其他疾病的可能性（即，阿尔茨海默病）。