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.
The proposed research is relevant to public health because of the enormous burden of disease resulting from traumatic brain injury (TBI) with 1.7 million adults suffering from TBI each year. TBI is a leading cause of death and disability, and currently, there are no specific therapies. Determining which cells are responsible for IL-1RI- signaling-induced neuroinflammation and neurodegeneration following TBI, may ultimately assist with the development of effective IL-1 blocking strategies.
