The Role of NFkB in Chronic Inflammation, Microglia Priming, and Neuropsychiatric Complications Following Diffuse Traumatic Brain Injury

Ohio State University, Columbus OH

Investigators

Abstract

Project Summary/Abstract Traumatic brain injury (TBI) is one of the foremost causes of death and disability in the United States. Most brain- injured individuals (~70%) develop neuropsychiatric or neuropathological complications, including depression, cognitive decline, epilepsy, or neurodegenerative disease, that negatively affect health and lifespan. Microglia are the resident innate immune cells of the brain and respond to insults, like TBI, that cause cell damage. While an early inflammatory response is often beneficial, chronic inflammation is detrimental and prevents return to brain homeostasis. Microglia reactivity is evident long after injury, and microglia are chronically hyper-reactive, or “primed,” to respond to secondary challenges. Secondary challenges include infections, which are common in the general population. In experimental studies, hyper-reactivity of microglia after TBI is associated with exacerbation of depressive-like behaviors, cognitive decline, and development of epilepsy. Though TBI is highly prevalent and associated with chronic disability, there are no current FDA-approved treatments for improving long-term outcomes. Furthermore, the link between inflammation after TBI, microglia priming, and poor long- term recovery is not understood. In this proposal, I will explore the role of NFkB, a prominent mediator of inflammatory gene expression, in propagating chronic microglia primed profiles and hyper-reactivity to secondary challenges. In Aim1, I will determine the therapeutic potential of an NFkB inhibitor to prevent chronic microglia activation and neuropathology (Aim1a), as well as microglia hyper-reactivity to secondary immune challenge associated with exacerbated sickness and depressive-like behaviors (Aim1b). In Aim2, I will focus on mechanism by using transgenic mice to determine if microglia-specific NFkB activation drives inflammation after TBI (Aim2a) and if microglia-NFkB activation contributes to epigenetic modifications in microglia that underlie enhanced reactivity (Aim2b). To complete these aims, I will have the support of 2 sponsors, as well as consultation with my other 3 committee members and bioinformatics experts at OSU. I am accomplished in several techniques that will be used throughout this proposal (midline fluid percussion injury, nCounter NanoString for gene expression analyses, immunofluorescent labeling, imaging, and quantification of gliosis) but will additionally add techniques to my skillset, including bulk RNA-sequencing, multi-ome single-nuclei RNA- and ATAC-sequencing, depressive behavioral assays, and neuropathology assessments. With the support of multiple OSU Core Facilities and Shared Resources (10X Genomics Platform, Flow Cytometry Core, and the OSU Comprehensive Cancer Center Genomics Shared Resources) and experts in these areas, I anticipate full completion of these aims, which will support at least one first-author publication. Attaining an F31 NRSA fellowship and completing these aims will make me a competitive postdoc applicant and position me to obtain future funding as I continue my career development into an independent academic researcher.