Date of Completion


Document Type

Honors College Thesis



Thesis Type

Honors College

First Advisor

Sayamwong Hammack

Second Advisor

Kalev Freeman

Third Advisor

Nicholas Klug


endothelium, traumatic brain injury, neuroinflammation, histones, membrane permeability, calcium signaling


Histone proteins, normally associated with chromatin structure, are released into the bloodstream following traumatic brain injuries (TBIs). Increased circulating histone concentrations in TBI patients are correlated with endothelial cell changes, neuroinflammation, and worse clinical outcomes. The mechanisms of histone-induced endothelial damage are not well understood, which limits the development of neuroprotective treatments. Here, we tested the hypothesis that histones cause calcium-dependent alterations in the endothelial cell membrane. Live cell video microscopy was used to track a fluorescent membrane dye during exposure of endothelial cells to extracellular histones. Histone exposure induced signs of retraction, membrane thickening, and blebbing that peaked approximately 40 minutes. Notably, membrane changes only became apparent approximately 20 minutes after histone exposure, later than the calcium oscillations produced by histones, which begin within 1-2 minutes. These changes were exacerbated in the absence of extracellular calcium and were completely blocked in the presence of the non-specific cation channel blocker Gadolinium (Gd3+). These studies provide novel evidence that native cation channels or newly inserted pores may participate in the production of histone-induced endothelial membrane permeability. Identification of these membrane-altering mechanisms may provide targets to prevent cerebrovascular inflammation after trauma, which could help improve brain injury outcomes.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Available for download on Saturday, December 14, 2024