Astrocyte-Specific IL-1RI Signaling Effects Following Traumatic Brain Injury

摘要 拟议的导师奖的目标有两个：1)为密集的导师提供保护时间 研究将Newell博士培养成一名独立的内科科学家，专注于免疫反应 创伤性脑损伤(TBI)和2)确定驱动IL-1RI诱导的细胞类型特异性机制 颅脑损伤后的炎症和神经毒性。在美国，170万成年人和60万儿童遭受 每年从TBI获得的。不幸的是，脑损伤的药物治疗是不存在的。治疗策略 在颅脑损伤后，目标特定的二次损伤级联反应是非常需要的。IL-1和IL-1介导的炎症反应 其他促炎细胞因子是一种潜在的继发性损伤途径。使用液体撞击伤 小鼠颅脑损伤模型建立局灶性弥漫性损伤伴发炎症反应 类似于人类脑外伤的情况。我们最近发现，对IL-1RI信号的遗传阻断导致 减少脑外伤后的神经炎症反应，改善认知功能。这项提议的假设是 星形胶质细胞特异性IL-1RI信号导致直接神经毒性以及小胶质细胞和白细胞 激活。拟议的研究将确定IL-1诱导的继发性损伤的星形胶质细胞特异性贡献。 后颅脑损伤。在第一个目标中，我们将研究IL-1RI信号对星形胶质细胞表型和 IL-1激活的星形胶质细胞对神经变性的影响。在第二个目标中，我们将研究 星形胶质细胞IL-1RI信号在脑外伤后小胶质细胞激活和脑白细胞募集中的作用。同时 此外，拟议的项目旨在为应聘者提供关键的职业发展培训。这个 建议书建立在候选人对TBI的既定兴趣以及她之前在TBI建模和培训方面的培训 神经免疫学。应聘者将由具有丰富经验的资深教员指导 神经科学、神经免疫学和临床前脑损伤研究。通过她导师的专业知识 委员会，特殊的科学环境，正规的课程和获得的科学技能，纽威尔博士将 在辅导期结束时，作为一名发展中的独立内科医生-科学家做好准备。

Abstract The goals of the proposed mentored award are two-fold: 1) to provide protected time for intensive mentored research to develop Dr. Newell into an independent physician-scientist with a focus on the immune response to traumatic brain injury (TBI) and 2) to identify cell-type specific mechanisms that drive IL-1RI induced inflammation and neurotoxicity following TBI. In the United States, 1.7 million adults & 600,000 children suffer from TBI each year. Unfortunately, pharmacologic therapies for TBI are non-existant. Treatment strategies that target specific secondary injury cascades that follow TBI are critically needed. Inflammation driven by IL-1 and other pro-inflammatory cytokines is one potential secondary injury pathway. Using a fluid percussion injury model of TBI in mice, a mixed focal and diffuse injury is created with an accompanying inflammatory reaction similar to what occurs in human TBI. We have recently shown genetic blockade of IL-1RI signaling resulted in decreased neuroinflammation and improved cognitive function post-TBI. The hypothesis of this proposal is that astrocyte-specific IL-1RI signaling results in direct neurotoxicity as well as in microglial and leukocyte activation. The proposed studies will identify astrocyte-specific contributions of IL-1 induced secondary injury post-TBI. In the first aim, we will examine the impact of IL-1RI signlaling on astrocyte phenotype and the impact of IL-1 activated astrocytes on neurodegeneration. In the second aim, we will examine the impact of astrocyte IL-1RI signaling on microglial activation and brain leukocyte recruitment following TBI. At the same time, the proposed project is designed to provide critical career development training to the candidate. The proposal builds upon the candidate's established interest in TBI and her prior training in TBI modeling and neuroimmunology. The candidate will be mentored by senior faculty members with extensive experience in neuroscience, neuroimmunology, and pre-clinical TBI research. Through the expertise of her mentoring committee, exceptional scientific environment, formal coursework, and acquired scientific skills, Dr. Newell will be well positioned as a developing independent physician-scientist by the conclusion of the mentoring period.