Neuron-specific effects of IL-1B

描述（由申请人提供）：炎症是脑损伤的结果，并导致炎性细胞因子的产生，这有助于损伤的进展。最有效的炎性细胞因子之一是白细胞介素-1（IL-1），其由许多类型的脑损伤诱导，并且可以增强神经元损失。IL-1抑制剂已被建议作为脑损伤后减轻神经元损失的治疗工具。然而，IL-1在生理条件下也在脑中表达，并且可能在介导正常海马功能中发挥作用。我们以前已经证明，IL-1？激活不同的信号通路，在神经元与神经胶质细胞在大脑中。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这种关键细胞因子的生理学与病理生理学作用至关重要。IL-1通过由1型IL-1受体（IL-1 R1）和IL-1受体辅助蛋白（IL-1 RAcP）组成的受体复合物发出信号。一种新的异构体的IL-1 RAcP，称为AcPb，已被确定，是专门在中枢神经系统神经元中表达，提供了一个新的机会，研究机制的神经元特异性IL- 1的行动。为了鉴定神经元特异性IL-1 RAcPb的功能，我们将从AcPb-/-小鼠建立神经元培养物，与野生型神经元和缺乏两种蛋白质亚型的神经元（AcP-/-）进行比较。IL-1的作用将分析这些神经元上的AcPb，以确定AcPb在介导神经元特异性信号通路中的作用，以及对神经元功能的影响。

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.