The aim of this project is to understand how Fc receptors communicate intracellular signals to initiate mast cell activation leading to inflammation. Fc receptors are key players in autoimmune diseases like systemic lupus erythematosus and in allergic disease. We have focused on how receptor activity is regulated for signaling proteins serving as possible links from Fc receptor to gene expression and mast cell degranulation, in order to help identify potential therapeutic targets in autoimmune and allergic disease. Results: The objectives of the past year were met in the following manner. First, studies on how the IgE receptor can distinguish between high- and low-affinity antigens were initiated as well as studies aimed at therapeutic intervention in mast cell function. These studies led us to explore the use for adaptor molecules in mast cells, and showed that the difference in affinity is interpreted into different usage of molecular signaling pathways. In addition, our studies using a parental compound that disrupts lipid raft integrity has demonstrated that such compounds inhibit mast cell degranulation. Additional work explored whether other stimuli that lead to mast cell activation functioned through the use of Lyn or Fyn. This work demonstrates that depending on the stimulus dominance of kinase usage may differ. Conclusions and Significance: In summary, our findings support the view that different stimuli can elicit specific responses through the use of particular molecular signaling modules. These findings provide new avenues for future exploration towards understanding the role of IgE Fc receptors in health and disease.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2013
Total Cost
$499,921
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
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Suzuki, Ryo; Leach, Sarah; Liu, Wenhua et al. (2014) Molecular editing of cellular responses by the high-affinity receptor for IgE. Science 343:1021-5
Alvarez-Errico, Damiana; Lessmann, Eva; Rivera, Juan (2009) Adapters in the organization of mast cell signaling. Immunol Rev 232:195-217
Gilfillan, Alasdair M; Rivera, Juan (2009) The tyrosine kinase network regulating mast cell activation. Immunol Rev 228:149-69
Rivera, Juan; Fierro, Nora A; Olivera, Ana et al. (2008) New insights on mast cell activation via the high affinity receptor for IgE. Adv Immunol 98:85-120
Rivera, Juan; Tessarollo, Lino (2008) Genetic background and the dilemma of translating mouse studies to humans. Immunity 28:1-4