Astrocyte-specific IL-1RI signaling effects following traumatic brain injury

摘要 建议的指导奖的目标有两个方面：1）为密集的指导提供受保护的时间 将纽韦尔博士发展成为一名独立的医学科学家，专注于免疫反应， 创伤性脑损伤（TBI）和2）确定驱动IL-1 RI诱导的细胞类型特异性机制 炎症和神经毒性。在美国，170万成年人和60万儿童遭受 每年的TBI不幸的是，TBI的药物治疗是不存在的。的治疗策略 TBI后靶向特异性继发性损伤级联是迫切需要的。由IL-1驱动的炎症和 其它促炎细胞因子是一种潜在的继发性损伤途径。利用液压冲击伤 在小鼠TBI模型中，产生混合的局灶性和弥漫性损伤，伴随炎症反应 类似于在人类TBI中发生的情况。我们最近发现，IL-1 RI信号传导的基因阻断导致 减少神经炎症和改善TBI后的认知功能。这一提议的假设是， 星形胶质细胞特异性IL-1 RI信号传导导致直接神经毒性以及小胶质细胞和白细胞 activation.这项研究将确定星形胶质细胞特异性IL-1诱导的继发性损伤 创伤性脑损伤后在第一个目标中，我们将研究IL-1 RI信号转导对星形胶质细胞表型的影响，以及IL-1 RI信号转导对星形胶质细胞表型的影响。 IL-1激活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-1 RI信号转导对TBI后小胶质细胞活化和脑白细胞募集的影响。在同一 同时，拟议项目旨在为候选人提供关键的职业发展培训。的 提案建立在候选人对TBI的既定兴趣和她之前在TBI建模方面的培训基础上， 神经免疫学候选人将由具有丰富经验的资深教师指导， 神经科学、神经免疫学和临床前TBI研究。通过她的专业指导 委员会，特殊的科学环境，正式的课程，并获得科学技能，纽韦尔博士将 在指导期结束时，作为一名发展中的独立医生-科学家处于有利地位。

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.