Sunday, May 18, 2025
5/18/2025
Targeting mechanisms of glycosaminoglycan accumulation and neurobehavioral dysfunction to improve outcomes from traumatic brain injury - Abstract Traumatic brain injury (TBI) is a chronic health condition affecting over 70,000 individuals per year. Multiple lines of evidence suggest TBI as a notable risk factor for the development of age-related disease through converging biological mechanisms that are poorly understood. The pathophysiological mechanisms associated with the onset and progression of age-related diseases are not completely understood. Therefore, a dire need for innovative approaches to better understand the biological mechanisms induced by TBI is required for clinical success to reduce the development of age-related disease. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a biomarker for TBI, and functions to maintain homeostasis of intracellular components. TBI upregulates brain levels of prostaglandins (PG), which have been shown to interact with UCHL1 and cause neuronal dysfunction, and possibly vascular dysfunction. We recently discovered a progressive accumulation of sulfated chondroitin- sulfate glycosaminoglycans (CS-GAGs) in UCHL1 positive cells of mice exposed to TBI. Directed mutations to the cysteine 152 residue of UCHL1 (C152A) can mitigate neurobehavioral dysfunction in mice exposed to TBI by reducing PG-UCHL1 interactions. Our Preliminary Data show reduced CS-GAG accumulation in the brains of C152A mice acutely following TBI compared to wildtype control mice. We hypothesize PG-UCHL1 interactions to mediate TBI-induced BBB disruption, CS-GAG sulfation/accumulation, and neurobehavioral dysfunction. Humans with a history of TBI often present with vascular and neuronal dysfunction, which are associated with age-related disease and have yet to be treated effectively. In this proposal, we will investigate whether inhibition of PG-UCHL1 interactions with indomethacin (INDO) and a UCHL1 mutant mouse (C152A) will attenuate TBI-induced vascular and neuronal dysfunction. Many studies, including ours, have shown preclinical TBI models to induce BBB disruption, CS-GAG sulfation/accumulation, and neurobehavioral dysfunction. We seek to elucidate a novel mechanism of TBI-induced vascular and neuronal dysfunction. Understanding the mechanism(s) of CS-GAG sulfation/accumulation will lead to novel therapeutic strategies to stop or reverse the course of age-related diseases associated with TBI. In addition, determining whether PG-UCHL1 interactions can modulate BBB disruption, CS-GAG sulfation/accumulation and neurobehavioral dysfunction would implicate new treatment strategies for predictable outcomes of TBI and age- related disease. More specifically, we seek to determine 1) whether a selective inhibitor for PG synthesis is sufficient to mitigate vascular and neuronal dysfunction, and 2) whether PG-UCHL1 interactions are required for TBI-induced BBB disruption, CS-GAG sulfation/accumulation and neurobehavioral dysfunction. If fully successful, results will suggest PG-UCHL1 interactions to play a major role in BBB disruption, CS-GAG sulfation/accumulation and neurobehavioral dysfunction and provide a novel therapeutic strategy to prevent, or slow the progression of age-related diseases associated with TBI.
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