Asthma is a common disease that consists of many phenotypes. Although corticosteroids (CS) are the mainstay of treatment for asthma, several phenotypes are particularly resistant to this therapy, leading to severe asthma (SA), a form of asthma with particularly high cost, morbidity and mortality. These patients have few therapeutic options currently available to them, and the underlying pathobiology for this severe, CS resistant disease is not understood. The immunology of asthma has classically been described as involving an ?allergic? signature with elevated levels of the type 2 cytokines interleukin-4, 5 and 13. However, it is becoming increasingly clear that not all patients harbor this same immunologic pathway. Recently published research from our laboratories have demonstrated elevated levels of interferon-gamma (IFN-?) and interlekin-27 (IL-27) in the airways of patients with severe asthma (SA). Interestingly, this particular combination of cytokines was previously shown in mouse lung macrophages to prevent nuclear translocation of the glucocorticoid receptor (GR) after binding corticosteroids, a step necessary for the activation of target genes and repression of pro- inflammatory genes that mediate the therapeutic effects of CS. In our own studies, we have demonstrated that these cytokines cause the same block in nuclear accumulation of GR in T cells, the key source of IFN-??in SA. We have also demonstrated lower lung expression of a GR-target gene, DUSP1, which mediates anti- inflammatory actions of CS, in our newly established mouse model of SA as compared to its expression in a model of milder asthma. We, therefore, hypothesize that the combination of IFN-? and IL-27 prevents the dissociation of GR from the multi-protein complex that normally retains it in the cell cytoplasm in the absence of CS. This cytokine-induced effect creates an unopposed inflammatory state that drives a SA phenotype with poor response to CS therapy. To address our hypothesis we will:
Specific Aim 1. Identify the mechanism by which the combination of IFN-? and IL-27 inhibits nuclear translocation of GR and its downstream effects on GR function.
Specific Aim 2. Confirm impaired GR function in a newly established mouse model of severe asthma. This project will allow the candidate as a physician scientist in training working towards a career in translational research to gain experience in both basic science and translational research. Although he has previously worked in a basic science setting, training in new immunological and molecular techniques proposed herein as well as in mouse models of disease will significantly augment his prior knowledge and provide a solid basic science foundation going forward. His mentors Dr. Anuradha Ray and Dr. Sally Wenzel have extensive knowledge and experience in the techniques, data analysis and scientific thought necessary for him to continue to develop on a track towards independent research. Furthermore, the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh provides strong support and resources to assist its post-doctoral scholars to develop as successful independent physician scientists.
Asthma is a common disease and severe asthma is particularly resistant to current therapies including corticosteroids (CS), leading to increased cost, morbidity and mortality. Our lab has recently shown that the cytokines interferon-gamma (IFN-?) and interleukin-27 (IL-27) are elevated in severe asthma. The combination of these two cytokines blocks the nuclear translocation of the glucocorticoid receptor (GR), which may explain poor response of severe asthmatics to CS therapy. We propose in vitro and in vivo studies using our newly established mouse model of severe asthma to determine the mechanism of failed GR translocation and its effect on downstream targets of GR.
|Gauthier, Marc; Chakraborty, Krishnendu; Oriss, Timothy B et al. (2017) Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias. JCI Insight 2:|