Undergraduate Honors Theses

Thesis Defended

Spring 2019

Document Type

Thesis

Type of Thesis

Departmental Honors

Department

Biochemistry

First Advisor

Kristi Anseth

Second Advisor

Brian Aguado

Abstract

Surgery is currently the primary treatment option for aortic valve stenosis (AVS) patients, many of whom are ineligible for surgery and are left untreated. AVS is progression is known to differ between males and females, and an understanding of sex-specific mechanisms of disease progression is imperative in developing accurate treatment options for men and women. The development of a nonsurgical therapy for AVS patients requires a deeper understanding of the molecular and cellular mechanisms of AVS progression. Currently, the role of calcium phosphate nanoparticles detected in the aortic valve during early stages of AVS in influencing disease progression and valvular interstitial cell (VIC) activation to myofibroblasts is unknown. Here, we sought to characterize the effects of nanoscale stiffness cues on VIC activation to myofibroblasts and hypothesized that alterations in nanoparticle stiffness and size would modulate sex-specific VIC activation and deactivation. Engineered hydrogel cell culture platforms embedded with polystyrene nanoparticles (PS-NPs) of varying size were employed to probe the role of nanoscale stiffness cues in modulating sex-specific VIC activation to the myofibroblast state, while poly(ethylene glycol) (PEG) nanogels of varying stiffness were synthesized and embedded in hydrogels or suspended in VIC media to gain a deeper understanding of VIC response to nanoscale stiffness cues. Analysis of alpha-smooth muscle actin (αSMA) expression and stress fiber formation in VICs in response to nanoscale stiffness cues revealed sex-specific VIC activation and deactivation in response to stiff PS-NPs and PEG nanogels of varying stiffness. Our results support the hypothesis that altering the stiffness and size of nanoparticles might influence sex-specific VIC activation.

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