DOI

https://doi.org/10.25772/8ENX-7J66

Defense Date

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

John J Ryan

Abstract

Allergic disease is the 6th leading cause of chronic illness in the US and accounts for billions of dollars in healthcare annually. Mast cells are tissue resident innate immune cells linked to allergic disease and activated by IgE and other ligands. Upon activation, they release histamine, cytokines, chemokines, proteases, and lipid mediators evoking allergic symptoms. New ways of targeting mast cells could greatly benefit allergic disease therapy. Previous findings supported repurposing statin drugs, such as Fluvastatin, as a therapeutic treatment of allergic disease reduced allergic symptoms in vitro and in vivo. We found that Fluvastatin suppressed IgE-mediated mast cell activation by inhibiting isoprenylation of proteins. However, statin suppression is dependent on genetic background. To avert genetic background dependency, we tested the hypothesis that a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734) would suppress allergic disease without having variable efficacy. We show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production similar to Fluvastatin in bone marrow derived mast cells from multiple genetic backgrounds. FGTI-2734 also significantly reduced cytokine production from human derived skin mast cells stimulated through the IgE receptor. We show that FGTI 2734 suppressed a mast cell-dependent model of IgE-mediated anaphylaxis in vivo in multiple genetic backgrounds. Among the >400 proteins targeted by prenylation, Ras family proteins have been shown to play a substantial role in IgE-mediated mast cell signaling. We found that loss of K-Ras, but not N-Ras, can mimic the effects of statins on IgE-mediated mast cell activation, suggesting a differential role of K-Ras and N-Ras in mast cell function. We show that in an airway model of allergic disease, FGTI-2734 treatment can significantly reduce airway inflammation and hyperresponsiveness. These data indicated that dual farnesyl and geranylgeranyl transferase inhibitors may be an effective therapeutic treatment for mast cell-associated diseases.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

2-21-2023

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