Friday, May 10, 2024
5/10/2024
PROJECT SUMMARY/ABSTRACT The increasing prevalence of both food and airway allergy in the last half-century is indicative of a critical need to understand the underlying biology and develop effective treatments. Crosslinking of the antibody isotype IgE on mast cells and basophils is directly responsible for allergic symptoms, signifying a critical role for IgE in the pathophysiology of allergy. Allergen-specific IgE and the corresponding allergies can persist for a lifetime. However, the mechanisms that govern the catabolism of IgE and distinguish it from other antibody isotypes, such as IgG, remain poorly understood. This research project seeks to uncover the cellular and molecular factors responsible for IgE catabolism. Regulation of IgG half-life is of interest for both improving current monoclonal therapeutics and treating autoimmunity; targeting IgE in a similar fashion could allow for specific control of pathogenic IgE. A striking finding from this proposal using transgenic mice is that the two canonical receptors for IgE, FceRI and FceRII, are dispensable for controlling the half-life of IgE in circulation, which is much shorter than that of IgG. IgE is primarily observed in a cell-bound state, which contrasts with the predominance of IgG in soluble form. IgE also possesses unique sugar modifications known as glycans, which affects its cognate receptors. Preliminary data generated by the applicant shows IgE bound to the surface of macrophages of the spleen and liver. As such, this proposal hypothesizes that IgE is recognized by novel receptors on macrophages in a glycan-dependent manner. The experiments of Aim 1 seek to investigate the receptors and cell types directly responsible for IgE catabolism through high-throughput yeast display, single- cell RNA sequencing (scRNA-seq), and radioactive tracing. In particular, the role of spleen and liver-resident phagocytes in this process will be studied using transgenic mouse models. Aim 2 of the proposal focuses on characterizing the impact of IgE glycosylation on catabolism. The effect of IgE oligomannose modifications on its binding to receptors and its clearance kinetics will be evaluated using flow cytometry and fluorescence kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) analyses will be used to investigate the regulation of IgE plasma cell enzymatic machinery on glycosylation. Collectively, these data will uncover key components of the signaling networks controlling IgE catabolism. In particular, the identification of a novel receptor could lead to the development of new therapeutics targeting pathogenic IgE. The applicant’s team of mentors has a diverse set of expertise that will facilitate the success of the project and the applicant’s development into an independent researcher in Type II inflammation.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
