Neuron-specific effects of IL-1B

IL-1B 的神经元特异性作用

• 批准号: 8225773
• 负责人: WILMA J FRIEDMAN
• 金额: $ 23.13万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225773
• 关键词: Astrocytes; Attenuated; Binding; Brain; Brain Injuries; Cells; Complex; Disease; Event; Goals; Hippocampus (Brain); Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukins; Long-Term Potentiation; Mediating; Microglia; Mus; Neuroglia; Neurons; Outcome; Physiological; Play; Population; Production; Protein Isoforms; Proteins; RNA Splicing; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Therapeutic; Variant; Wild Type Mouse; cell type; cytokine; hippocampal pyramidal neuron; inhibitor/antagonist; interleukin-1 receptor accessory protein; neuron loss; novel; receptor; response; synaptic function; therapeutic development; therapy development; tool

DESCRIPTION (provided by applicant): Inflammation occurs as a consequence of brain injury, and results in the production of inflammatory cytokines, which contribute to the progression of the insult. One of the most potent inflammatory cytokines is interleukin-1 (IL-1), which is induced by many types of brain injury and can potentiate neuronal loss. IL-1 inhibitors have been suggested as therapeutic tools following brain injury to attenuate neuronal loss. However, IL-1¿ is also expressed in the brain under physiological conditions, and may play a role in mediating normal hippocampal function. We have previously demonstrated that IL-1¿ activates distinct signaling pathways in neurons versus glial cells in the brain. Therefore, to assess the consequences of inflammation that occur following injury, and the potential therapeutic value of inhibiting inflammation, it is critical to understand the cell-specific consequences and to distinguish physiological versus pathophysiologial roles for this key cytokine. IL-1 signals via a receptor complex composed of the type 1 IL-1 receptor (IL-1R1) and the IL-1 Receptor Accessory Protein (IL-1RAcP). A novel isoform of the IL-1RAcP, termed AcPb, has been identified that is expressed exclusively in CNS neurons, providing a new opportunity to investigate the mechanisms governing neuron-specific IL- 1 actions. To identify the function of the neuron-specific IL-1RAcPb we will establish neuronal cultures from AcPb-/- mice compared to wild type neurons and to neurons lacking both isoforms of the protein (AcP-/-). The effects of IL-1¿ on these neurons will be analyzed to determine the role of AcPb in mediating neuron-specific signaling pathways, and the consequences for neuronal function. PUBLIC HEALTH RELEVANCE: Interleukin-1 is a potent and pleiotropic cytokine that is induced in the brain by injury, disease, and stress. The recent identification of a neuron-specific isoform of a key IL-1 signaling protein provides a novel opportunity to investigate mechanisms governing the specific effects of IL-1 on neuronal function. These studies may also facilitate the development of therapeutic approaches to distinguish physiological versus pathophysiologial roles for this key cytokine in the brain.

描述（由申请人提供）：炎症是脑损伤的结果，并导致炎症细胞因子的产生，这导致损伤的进展，最有效的炎症细胞因子之一是白细胞介素-1 (IL-1)。 ，它是由多种类型的脑损伤引起的，并且可以增强神经元损失，已被建议作为脑损伤后减轻神经元损失的治疗工具。在生理条件下，IL-1 也在大脑中表达，并且可能在调节正常海马功能中发挥作用。激活神经元与大脑神经胶质细胞中不同的信号通路因此，为了评估损伤后发生的炎症的后果以及抑制炎症的潜在治疗价值，了解细胞特异性后果并区分生理与神经胶质细胞至关重要。这种关键细胞因子的病理生理作用通过由 1 型 IL-1 受体 (IL-1R1) 和 IL-1 受体辅助蛋白 (IL-1RAcP) 组成的受体复合物发出信号。 IL-1RAcP（称为 AcPb）已被鉴定为仅在 CNS 神经元中表达，这为研究控制神经元特异性 IL-1 作用的机制提供了新的机会。为了确定神经元特异性 IL-1RAcPb 的功能，我们将建立。 AcPb-/- 小鼠的神经元培养物与野生型神经元和缺乏两种蛋白同工型的神经元 (AcP-/-) 的影响进行比较。将分析这些神经元上的 AcPb 在介导神经元特异性信号传导途径中的作用以及对神经元功能的影响。 公共健康相关性：IL-1 是一种强效的多效性细胞因子，可在大脑中因损伤、疾病和压力而诱导产生。最近鉴定出关键 IL-1 信号蛋白的神经元特异性亚型，为研究提供了新的机会。这些研究还可能促进治疗方法的开发，以区分这种关键细胞因子在大脑中的生理作用和病理生理作用。