COMPUTATIONAL SCREENING FOR NOVEL INHIBITORS OF PROTEINS IN THE MAST CELL DEGRANULATION PATHWAY

Gemstone Team CASCADEAllergies are a pervasive issue and require novel ways of alleviating symptoms. Existing treatments focus on symptom management and immunotherapy in response to an allergic reaction. However, there is also the potential for prophylactic treatment that inhibits molecules involved in the mast cell degranulation pathway, which causes allergic symptoms. We identified potential target proteins downstream of this pathway including PKC, PLCγ, and PI3K isoforms, the activation of which results in the degranulation of mast cells. We computationally modeled protein-inhibitor binding interactions and identified inhibitors with the predicted highest binding affinity to the target pathway proteins. For the most efficient inhibitors, we extended our analysis by construction of analogs to determine which chemical properties of the inhibitors contributed to the highest binding affinity. The identified possible inhibitors have the potential to hinder mast cell degranulation, limit histamine and cytokine release, and therefore prevent allergic symptoms, making them ideal targets for future pharmacology research

Inhibiting Degranulation in Immune Cell Signaling Pathways

Allergies are a pervasive issue and require novel ways of alleviating symptoms. Existing treatments are focused on symptom management and immunotherapy, but there is also potential to target the molecules involved in the downstream pathway, particularly the PLCγ enzymatic pathway. Our research aimed to identify important target molecules involved in this pathway that result in the degranulation of mast cells. We intended to inhibit these molecules in order to hinder mast cell degranulation and therefore prevent allergic symptoms. Our results were tested and measured in MC/9 (mouse mast cell) and RBL-2H3 (rat basophilic) cell lines with multiple cell degranulation assays such as the beta-hexosaminidase and tryptase assay. The results were evaluated based on the comparative effect as well as specificity of inhibitors on mast cell degranulation. We aim to find the most ideal inhibitor for the PLCγ, SK, S1P2 enzymatic pathways in the signalling cascade in order to most effectively reduce degranulation and thus reduce the allergic response.Mosser Lab, Gemstone Honors Program, and our generous LaunchUMD donor