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Abstract
Allergic disease is driven by cell signaling cascades that activate immune cells. One key player is mast cells, which is activated by IgE antibodies signaling through the high affinity IgE receptor, FceRI. Therefore, targeting FceRI-mediated cascades can offer for novel treatments for allergic disease. Statins have been demonstrated to reduce the severity of asthma, a common allergic airway disease. Statins are an FDA approved class of drugs with the intended purpose of lowering blood cholesterol. We previously found that while statins inhibit mast cell function in allergic disease, these anti-inflammatory effects vary widely amongst differing mouse strains and human donors, suggesting genetic variability. This project sought to overcome statin resistance by acting “downstream” in the cholesterol synthesis pathway on protein isoprenylation pathways. The logic is that isoprenylated proteins are critical for FceRI signaling, thus blocking this step of protein modification should reduce FceRI-mediated mast cell function. The novel FGTI-2734 drug was used to suppress the isoprenylation enzymes farnesyl transferase and geranylgeranyl transferase. FGTI-2734 reduced IgE-mediated mast cell degranulation and cytokine and chemokine secretion. Additional work found that both transferases must be targeted to produce these anti-inflammatory effects. Furthermore, we revealed that the K-Ras protein is an isoprenylation target that is essential for IgE-mediated mast cell function. Collectively, these studies demonstrate the translational potential of the novel drug FGTI-2734 and suggest it acts by suppressing isoprenylation of proteins critical for mast cell function, including K-Ras.
Publication Date
2023
Disciplines
Amino Acids, Peptides, and Proteins | Medical Cell Biology | Medical Immunology | Organic Chemicals
Current Academic Year
Junior
Faculty Advisor/Mentor
John J. Ryan
Rights
© The Author(s)
Included in
Amino Acids, Peptides, and Proteins Commons, Medical Cell Biology Commons, Medical Immunology Commons, Organic Chemicals Commons