? PROJECT 1 Disease-modifying or personalized preventive strategies for asthma remain elusive. Project 1 puts forward two aims to achieve these goals under the overarching hypothesis that pathologic oxidant mechanisms are central to pathogenesis of asthma. First, Project 1 proposes the concept of metabolic endotypes of asthma and investigates whether diet can modulate inflammatory responses, gene expression, and airway hyperreactivity. Our Cycle I studies indicate that cellular metabolism and oxidative potential are different in asthmatics as compared to healthy controls, and that Coenzyme Q administration re-establishes normal redox, suggesting mitochondrial mechanisms in the dis-equilibrium. In an early phase study, an alternate day diet ablates the classical TH2 gene expression signature present during standard American diet, and a subgroup of asthmatics lose hyperreactivity to methacholine. Preliminary data show mitochondrial DNA haplotypes that have greater uncoupling of oxidative phosphorylation carry asthma risk.
In aim 1, we test the hypothesis that alternate day caloric restriction benefits asthma through mechanisms that decrease oxidative metabolism, TH2 gene expression, and pro-inflammatory TH17 signaling pathways. We also test the complementary idea that mitochondrial haplotypes that confer asthma-risk may influence response to diet intervention. We propose to test these ideas through a longitudinal mechanistic trial: Metabolic Intervention to Reverse Asthma (MIRA). Second, Project 1 proposes to advance utility of urine bromotyrosine (BrTyr), a biomarker of oxidative- modifications produced by the activated eosinophil, as a major step forward to a personalized medicine strategy in asthma, in particular for application of biologically-based treatments. In Cycle I, we showed that BrTyr levels increase during asthma exacerbation, and high levels identify patients with poor control and at-risk of exacerbation. In preliminary studies, BrTyr is quantitatively related to asthma severity, and levels decrease in proportion to the improvement in FEV1 with parenteral corticosteroids.
In aim 2, we test the hypothesis that BrTyr will: (1) identify clinical responders to a TH2-targeted anti-IgE intervention in a longitudinal trial of BrTyr in Treatment Effectiveness of asthma [BrYTE]; and (2) be quantitatively related to asthma severity and control in collaborative studies with NIH asthma networks, industry studies, and in MIRA. Project 1 depends on expertise and resources of the program to establish mechanisms within clinical studies: Project 2 for TH17 mechanisms in metabolism and asthma, and Project 3 for biochemical mechanisms of airway hyperreactivity. Core A enables sharing of Project 1 clinical samples in order to facilitate translational and mechanistic experiments. Project 1 through Core B support has forged strong partnerships (Nestl, Procter&Gamble, Novartis, and Cleveland HeartLab) to implement strategies and products. The focus of translation and commercialization in Project 1 is to define the value proposition in support of development of food product(s) for caloric restriction days in aim 1 and the noninvasive prognostic/diagnostic test for asthma in aim 2.
? PROJECT 1 Based on scientific discoveries in Cycle I of the Program, Project 1 plans new strategies for asthma care including intermittent caloric restriction to reverse asthma inflammation and hyperreactivity, and a personalized medicine approach by validating a biomarker of eosinophil activation for effectiveness of biologic-based treatment of asthma.
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