Role of Neuronal p38 MAPK After Repetitive Mild TBI - PROJECT SUMMARY
Mild traumatic brain injuries (mTBIs) affect millions per year, leaving 10-40% of patients with long-lasting (>1
month) physical, emotional, psychological, and cognitive symptoms for which effective therapeutic strategies
are lacking. Moreover, repetitive mTBI (rmTBI) can lead to cumulative severity and duration of adverse
consequences. Clinical and preclinical studies have shown that the spectrum of neurological sequelae seen
post-injury cannot be explained by biomechanical impact forces alone. Injury mechanisms underlying
neurological symptoms after repetitive mild traumatic brain injury (rmTBI) are poorly understood and may be
distinct from more severe forms of TBI. Working together, Drs. Wood and Buckley (co-PIs) have recently
discovered that neuronal p38 MAPK phosphorylation is acutely up-regulated in mice predicted to have
worse cognitive outcomes after rmTBI. p38 MAPK is a stress-response pathway with a well-established pro-
inflammatory role in microglia after TBI. However, there is a gap in knowledge on the role of neuronal p38
MAPK phosphorylation in regulating response to injury that leads to cellular and cognitive dysfunction
after TBI. Our overall hypothesis is that p38 MAPK phosphorylation, especially within neurons, drives both 1)
acute changes in cytokine expression, microglia activation, and cerebral blood flow and 2) chronic changes in
microglia and cognitive deficits after rmTBI. Given limited knowledge on the role of neuronal phospho-signaling
in driving these neuroinflammatory, cognitive, and physiologic changes after TBI, the goal of this proposal is to
expand our knowledge on the role of p38 MAPK phosphorylation on brain sequalae following repetitive mild
TBI. Thus, the investigative team has designed specific aims to: (Aim 1) define the role of neuronal p38 MAPK
in driving neuroinflammation after rmTBI, including cytokine expression and microglial phenotype; (Aim 2)
define the role of neuronal p38 MAPK in driving longer term cognitive outcomes up to 12 weeks post injury,
test the ability of transient pharmacologic inhibition of p38 MAPK to protect cognitive outcomes, and determine
if microglia mediate the effects of neuronal p38 MAPK on cognitive outcomes; (Aim 3) determine if neuronal
p38 MAPK or a neuronally expressed vasomodulatory cytokine (IL-17) drive changes in CBF after repetitive
mild TBI. The proposed work will be completed by a team with expertise in systems analysis of neural immune
signaling (Wood), pre-clinical models of traumatic brain injury and measurement of CBF (Buckley), microglial
phenotyping (Rangaraju) and mechanisms of cerebral blood flow regulation (Jo). Completion of these aims will
yield unprecedented insight into the role of neuronal phospho-signaling in driving sequalae following repetitive
mild TBI. Moreover, since this work will test a translationally relevant drug for inhibition of p38 MAPK, success
of these aims will present a rapidly translatable approach to treatment of repetitive mild TBI.