Severe, corticosteroid-insensitive asthma is observed in ~ 10% of the asthma population but accounts for the majority of the morbidity, mortality and cost associated with the disease. For nearly 10 years our group has studied airway redox disturbances in adults and children with asthma through the NIH/NHLBI Severe Asthma Research Program (SARP). Through innovative metabolomics and redox biochemistry, methodologies that are a strength and unique to our collaborative efforts, we identified clinically relevant phenotypes of asthma. The phenotypes are defined by biomarkers specific to underlying biochemical mechanistic abnormalities, including eosinophil-mediated oxidation, depletion of antioxidants and protective airway S-nitrosothiols, and airway acidification. Here, we propose to study a new component that is informative for longitudinal assessment of severe asthma phenotypes: gender effects. Severe asthma affects boys more than girls;however, severe asthma in adults is a disease of women. The age-dependent change in gender predilection is one of the largest signals in severe asthma epidemiology, but remains understudied. We reason that identification of the metabolic mechanism(s) underlying onset of severe asthma in young women during adolescence, and resolution of severe asthma in boys, will reveal fundamental pathophysiology of severe asthma. Importantly, we aim to develop clinical testing procedures to accurately assign metabolic asthma phenotypes;and to follow patients in each phenotype to uncover clinical longitudinal outcomes. At the conclusion of the project, we anticipate that we will have 1) developed clinically relevant tests to identify severe asthma phenotypes;2) determined the longitudinal outcome of the phenotypes;and 3) identified the mechanisms underlying the preponderance of women in the severe asthma population.
Severe asthma is a major public health challenge. Whereas only 10 to 15% of all asthmatics have severe asthma, these patients account for a relatively large fraction of the total health care costs attributed to asthma. This application will focus on the development or clinically relevant metabolic tests to identify subphenotypes of adults and children with severe asthma and will lead to new targeted innovative treatments.
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|Ash, Samuel Y; Rahaghi, Farbod N; Come, Carolyn E et al. (2018) Pruning of the Pulmonary Vasculature in Asthma. The Severe Asthma Research Program (SARP) Cohort. Am J Respir Crit Care Med 198:39-50|
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|Wisniewski, Julia A; Muehling, Lyndsey M; Eccles, Jacob D et al. (2018) TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J Allergy Clin Immunol 141:2048-2060.e13|
|Asosingh, Kewal; Weiss, Kelly; Queisser, Kimberly et al. (2018) Endothelial cells in the innate response to allergens and initiation of atopic asthma. J Clin Invest 128:3116-3128|
|Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386|
|DeBoer, Mark D; Phillips, Brenda R; Mauger, David T et al. (2018) Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. BMC Pulm Med 18:58|
|Denlinger, Loren C; Phillips, Brenda R; Ramratnam, Sima et al. (2017) Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med 195:302-313|
|Modena, Brian D; Bleecker, Eugene R; Busse, William W et al. (2017) Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease. Am J Respir Crit Care Med 195:1449-1463|
|Ricklefs, Isabell; Barkas, Ioanna; Duvall, Melody G et al. (2017) ALX receptor ligands define a biochemical endotype for severe asthma. JCI Insight 2:|
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