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Midori Wasielewski Maeda
BME PhD Defense Presentation
Date: 2022-10-25
Time: 2:00 PM - 4:00 PM (EST)
Location / Meeting Link: Location: Petit Biotech Building, Rm 1128, Suddath Seminar Room Link:https://gatech.zoom.us/j/91893695401
Committee Members:
Shuichi Takayama, Ph.D. (Advisor); Julia Babensee, Ph.D.; Andres J. Garcia, Ph.D.; Jason S. Knight, M.D., Ph.D.; Rebecca D. Levit, M.D.
Title: Engineering a novel method for in vitro characterization of neutrophil extracellular trap (NETs) degradation
Abstract:
Neutrophil extracellular traps (NETs) are DNA webs cast by neutrophils during the innate immune response to injury and infection. An impaired ability to degrade NETs drives disease severity in thrombosis, autoimmune diseases, and COVID-19. NETs are difficult to observe in vitro and in vivo, therefore few clinical strategies exist to resolve impaired NETs degradation. In an effort to address the variability of NETs degradation protocols, this project aimed to design a standardized biomaterial-based assay to characterize NETs degradation in vitro. In Aim 1, we designed NETs-mimetic chromatin structures, termed DNA-Histone Mesostructures (DHMs) in a 96-well plate format and found a close resemblance to the morphology and properties of cell-derived NETs. In Aim 2 we developed a DHM degradation assay to characterize serum-mediated degradation. The defined initial DHM structures enabled real-time image-based monitoring of degradation, something that is difficult to do with NETs. Although DHMs were less susceptible to digestion by serum and nucleases than cell-derived NETs, they modeled the extent of degradation, thereby serving as a mimetic model. In Aim 3 we screened a panel of serum and neutrophil proteins and identified compounds that promote and inhibit degradation. Our findings suggest that DHM degradation involves protease digestion in addition to nuclease degradation. This work holds the potential to identify novel strategies to promote full NETs degradation.
