Chenxing Li
BME PhD Defense Presentation

Date: 2026-03-09
Time: 11:00am - 1:00PM
Location / Meeting Link: EBB CHOA, https://gatech.zoom.us/j/8836072444?omn=94365358356

Committee Members:
Levi Wood; Erin Buckley; Machelle Pardue; Srikant Rangaraju; Andrew Feola; Candace Floyd

Title: THE ROLE OF NEURONAL P38 MAPK IN REPETITIVE MILD TRAUMATIC BRAIN INJURY

Abstract:
Despite its high prevalence and impact on quality of life, effective clinical treatments for mTBI/rmTBI remain elusive, largely due to an incomplete understanding of the underlying injury mechanisms. Over the past decades, increasing evidence has implicated neuroinflammation as a key contributor to post-injury pathology. Within this response, intracellular signaling pathways such as p38 mitogen-activated protein kinase (MAPK) represent central, potentially targetable regulators of inflammatory signaling. Accordingly, there is a need for new therapeutic strategies targeting these pathways and for deeper mechanistic insight into the causal drivers of injury pathology. This dissertation investigates the role of neuronal p38α in rmTBI pathology with two main goals: (1) to advance our understanding of the molecular mechanisms that modulate rmTBI outcomes and (2) to identify a therapeutic approach that targets injury mechanisms. This work, for the first time, illuminates a neuron-driven causal mechanism for rmTBI, broadening current views of neuroinflammation by demonstrating the immunomodulatory role of neurons. Using an in vivo murine weight-drop model, we evaluated how rmTBI and p38 MAPK modulation affect outcomes spanning acute cytokine expression, glial reactivity, and transcriptomic changes, as well as long-term synaptic density and behavioral function. First, with a small-molecule p38 MAPK inhibitor administered 30 minutes post-injury, transient p38 MAPK inhibition mitigated most rmTBI-induced consequences, including synaptic loss, cytokine upregulation, microglial reactivity, functional deficits, and injury- associated transcriptomic alterations, while enhancing protective pathways. Next, using a transgenic model to selectively knock out p38α in neurons, we found that the rmTBI- induced neurological deficits observed in wild-type controls—including functional impairment, synaptic loss, microglial changes, cytokine upregulation, and reduced cerebral blood flow—were largely absent in mice with neuronal p38α knockout. Altogether, these findings identify p38 MAPK inhibition as a promising therapeutic strategy targeting injury-relevant molecular mechanisms after rmTBI and, for the first time, establish a causal role for neuronal p38α in rmTBI pathology. This work expands current understanding of neuroinflammation-driven neurological consequences in rmTBI, a prevalent yet understudied form of brain injury. Importantly, our results support the traditionally underappreciated role of neurons as active immunomodulators in the injury response, motivating future studies to define neuron-intrinsic immune signaling in other neurodegenerative diseases and to explore neuron-focused therapeutic approaches.