Friday, April 19, 2024
4/19/2024
Project Summary Despite the widespread availability of therapeutic agents, more than half of the 300 million people worldwide with asthma have inadequate control of their disease resulting in an increased risk of exacerbations and a large economic burden to the United States health care system. More effective and curative therapies are clearly needed and will best be identified by increasing our understanding of the pathogenic mechanisms of asthma. Allergy is a risk factor for the development of asthma, and most cases of asthma are allergic in origin. However, not all individuals with systemic allergen sensitization develop asthma symptoms upon allergen exposure. These allergic non-asthmatic individuals may develop allergic rhinitis in response to an allergen but do not have the lower respiratory tract symptoms characteristic of asthma. Interestingly, many allergic non-asthmatic patients will develop asthma symptoms over time, suggesting that the pathogenic mechanisms leading to asthma may be incremental and reversible. Thus, determination of factors that differentiate the asthma phenotype in allergic individuals could provide important insights into asthma pathogenesis and identify therapeutic targets. In health, airway epithelial cells (AEC) and airway mononuclear phagocytes (MNP) help to maintain tissue homeostasis and defend against pathogens. However, in asthma, AEC generate pro-inflammatory signals in response to allergens that then initiates and propagates a type 2 immune response in the lung via activation of MNP. Our published and preliminary studies demonstrate that the AEC and MNP have profoundly different reactions to allergens in allergic asthmatics (AA) compared to allergic non-asthmatic controls (AC), including differential gene expression and regulation of metabolic pathways, and an enhanced inflammatory response in allergic asthmatics. These studies suggest that AEC and MNP can undergo epigenetic modifications and metabolic reprogramming leading to a lasting immunological memory and enhanced response towards subsequent exposures. This functional reprogramming is called trained immunity, and while it has been studied in the context of infectious diseases, it has not been explored in the context of pulmonary inflammatory diseases such as asthma. Our hypothesis is that AEC and airway MNP cells in allergic asthmatic individuals have a trained immune response to allergens which drives the asthma phenotype. The specific aims are to: 1) Determine the transcriptional accessibility of gene loci in AEC and airway MNP from allergic subjects with and without asthma.; and 2) Compare the metabolic profile of AEC and airway MNP from allergic subjects with and without asthma. We will utilize nasal brushings and bronchoscopy to directly sample AEC and MNP and bronchoalveolar lavage fluid from AA and AC airways for single cell Assay for Transposase-Accessible Chromatin sequencing (scATAC- seq) and metabolomics to determine if there are fundamental differences in the gene regulatory and metabolic landscape of AEC and MNP between these groups.
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