Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Microbiology & Immunology
First Advisor
John J. Ryan
Second Advisor
Rebecca Martin
Third Advisor
Lisa Shock
Abstract
Allergic asthma is an inflammatory disease of the airway associated with sensitization to allergens and symptoms such as sneezing, wheezing, and airway hyperresponsiveness. The severity of this disease varies between sex, age, and race; therefore, understanding the signaling mechanisms driving allergic asthma is integral to developing targeted therapeutics. Mast cells (MC), an important effector cell in allergic disease, can be activated by interleukin (IL)-33, an alarmin released after cells have contact with cellular stressors including common allergens. In response to IL-33, MCs release inflammatory cytokines and lipid mediators. We previously found that statins suppress IgE-mediated MC activation by inhibiting protein isoprenylation. Therefore, we hypothesized that directly targeting the isoprenylation enzymes farnesyl transferase (FT) and geranylgeranyl transferase (GGT) would suppress IL-33-mediated MC function. We show that the dual transferase inhibitor FGTI-2734 decreased IL-33-mediated inflammatory cytokine secretion, effects that were mimicked by simvastatin. In contrast to the dual inhibitor, suppressing only FT or GGT had no effect on cytokine secretion. These data suggest that inhibiting farnesyl and geranylgeranyl transferases is a potential treatment for IL-33-mediated mast cell activation and allergic disease.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-13-2024