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; 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).

抽象的 神经炎症的管理是改善患者结局后的承诺目标 创伤性脑损伤（TBI）和大量证据表明针对白介素-1受体的疗法 （IL-1R1）途径可能控制神经炎症。尽管有希望，但仍有有限的尝试 向前移动抗Interleukin-1（IL-1）药物进行TBI神经保护。我们认为这是缺乏的关键原因 这个诺言目标的进步是对IL-1的机械基础的不完全理解 TBI后发出信号。众所周知，TBI的临床图片是不同原发性损伤的频谱 机制和伤害的严重程度，并且有必要将次要伤害机制理解为 它们与主要伤害有关。超过75％的TBI被归类为轻度。虽然并非所有的tbis都导致 神经变性，轻度TBI会导致脑萎缩和持续性认知功能障碍，并且 是阿尔茨海默氏病和相关痴呆症发展的已知危险因素。电流 TBI后IL-1 / IL-1R1信号传导的知识几乎完全是在现代对重度伤害之后的。 使用我们的新型遗传小鼠模型，该模型允许IL-1R1信号的细胞类型调节，我们的模型 由封闭的头部受伤引起的轻度TBI（CHI）我们将在我们的知识中解决这一基本差距 在轻度TBI之后测试IL-1R1的作用，并首次定义了一种细胞机制 轻度TBI后IL-1R1的病理作用。重要的是，我们令人兴奋的初步数据已经发现了 脑内皮在控制神经炎症中的关键作用，这取决于IL-1R1。我们的 初步结果使我们提出了总体假设： 轻度TBI是由神经炎症和血管功能障碍驱动的，可以通过 抑制IL-1R1。轻度TBI之后的IL-1R1的作用将需要参与 内皮细胞。我们将在以下目的中检验我们的假设： AIM 1：评估内皮IL-1R1信号传导在神经炎症馈电循环中的作用。 目标2：定义内皮IL-1R1信号传导在对CHI的血管反应中的作用。 目标3：描述内皮IL-1R1信号传导对合成可塑性和空间学习的作用 卡后的记忆。 这些研究的成功完成将增加我们对中期后IL-1R1作用的理解 TBI并定义了脑内皮在对轻度TBI的神经炎症反应中的作用。我们的结果 将填补有关如何最好地靶向神经炎症以实现神经保护的关键知识差距 轻度TBI之后，并可能与神经炎症相关的其他疾病（即阿尔茨海默氏病）。