Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Allergen-induced asthma is a chronic disease predominantly characterized by dysregulated type 2 inflammation in the lung. While the adaptive immune system has been implicated in asthma pathogenesis for many years, research over the last decade has recognized that Group 2 innate lymphoid cells (ILC2) are potent drivers of type 2 inflammation in the lung and major contributors to allergen-exacerbated asthma. ILC2 are similar in function to Th2-polarized CD4+ helper T cells in that they produce Type 2 cytokines like IL-5 and IL-13, but they lack rearranged antigen receptors and are instead activated predominantly by alarmin cytokines. While their pro-inflammatory potential and connection to asthma has been established, the precise mechanisms by which these cells are activated and proliferate in response to aeroallergens are ill defined. I have utilized the Collaborative Cross recombinant inbred mouse panel to map a quantitative trait locus (QTL) that associates with the number of lung ILC2, a function of activation and proliferation, in response to airway challenge with extract from the common environmental allergen Alternaria alternata (Alt Ex). The Collaborative Cross (CC) is an ambitious, multi-center mouse genetics project created to allow for the investigation of complex polygenic traits. The panel boasts over 50 recombinant inbred lines created from 8 founder strains (5 lab-derived, 3 wild-caught) that encompass >90% of the known genetic diversity in the Mus musculus species. I enumerated ILC2 after Alt Ex challenge in 45 unique founder and recombinant CC strains, and I successfully mapped a novel 0.343 megabase QTL associated with ILC2 number in the lung containing 72 protein coding genes. The goal of this proposal is to identify and define the precise function of the causative gene or genes within this QTL that contribute to ILC2 proliferation in response to aeroallergen challenge. I identified CD22, a Siglec family receptor that inhibits B cell proliferation, as the most biologically plausible of the 72 gene candidates. I hypothesize that CD22 is the causative gene driving the observed phenotypic differences among the CC lines and that CD22 signaling in ILC2 inhibits their activation and proliferation. I confirmed that CD22 is expressed on ILC2, and I observed differences in CD22 expression between CC strains that had high and low ILC2 number in response to Alt Ex challenge. I will further test this hypothesis with two specific aims. In Aim 1, I will perform experiments in our Alt Ex challenge model using CD22 knockout mice to investigate the effect of gene deletion on ILC2 proliferation in vivo. Further, I will utilize a CD22-blocking antibody to define the effect of receptor blockade on ILC2 proliferation. In Aim 2, I will continue to reduce the interval of my QTL to narrow the list of gene candidates through the phenotyping of additional mice. I will acquire Diversity Outbred (DO) mice and utilize my Alt Ex challenge model, increasing my fine mapping power and further defining my genes of interest. In completing these studies, I will characterize a previously unknown regulator of allergen-induced ILC2 number in the lung and potential therapeutic target in the treatment of allergen-exacerbated asthma.
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