The goal of this Program Project Grant (PPG) revised renewal application is to establish mechanisms underlying asthma inception and exacerbation during childhood and adolescence. The three projects and cores of this PPG application have collaborated extensively and effectively over the past decade using the ROI (COAST I) and PPG (COAST ll-lll) funding mechanisms and this integrated and multidisciplinary approach (immunology, microbiology, physiology, and genetic) has resulted in multiple novel and seminal observations into the inception of asthma. Our central theme is that human rhinovirus (HRV) infections during childhood and adolescence contribute mechanistically to the development of specific phenotypes of childhood wheezing and asthma (inception) due to abnormal host immune response """"""""pathways"""""""" that are independent, genetically regulated, and have HRV as a common intersection point. Furthermore, once asthma is established, our preliminary data suggest that HRVs interact with specific airway bacteria to modulate respiratory symptom severity and promote asthma exacerbations, and that immune response profiles can additionally modify these asthma phenotypes based on age and gender. The current PPG renewal application is highly innovative from the standpoints of original hypotheses, study design, and analytical approaches. First, our preliminary data has led to the hypothesis that risk for asthma inception is related to genetic variation in at least two independent """"""""pathways"""""""" that have HRV wheezing illnesses as a common link in early life. Second, from a study design standpoint, the extensive longitudinal immunologic, microbiologic, genetic and physiologic phenotyping that has and will continue to be performed provides a unique data set and future opportunity to integrate asthma phenotype development to age, gender, and to the natural history of asthma itself. Third, we propose to use a unique study design that will evaluate viral and bacterial (and the microbiome) interactions, vitamin D receptor genotype and vitamin D levels in both children with asthma and cohort control subjects as they relate to respiratory symptom burden and the development of asthma exacerbations. Fourth, from a technical perspective, we propose to use state-of-the-art genetic analyses that will involve miRNA evaluations, epigenetics, and gene expression studies all in the same airway samples (nasal epithelial cells). The proposed studies will provide greater mechanistic understanding and new approaches that are needed to address the important therapeutic gap in treatment and prevention of HRV and bacterial illnesses as they relate to both asthma inception and exacerbations.
The focus on human rhinovirus (HRV) infections as a pervasive risk factor for asthma is highly relevant from a public health perspective as the impact of HRV infections on asthma morbidity and respiratory disorders has raised substantial concerns. As such, mechanisms that underlie both asthma inception and asthma exacerbations will be extensively evaluated in this proposal. The proposed studies will provide insight into therapeutic approaches that will be relevant to both prevention of, and intervention for, asthma.
|Bashir, Hiba; Grindle, Kristine; Vrtis, Rose et al. (2018) Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens. J Allergy Clin Immunol 141:822-824.e9|
|Higano, Nara S; Bates, Alister J; Tkach, Jean A et al. (2018) Pre- and post-operative visualization of neonatal esophageal atresia/tracheoesophageal fistula via magnetic resonance imaging. J Pediatr Surg Case Rep 29:5-8|
|Higano, Nara S; Spielberg, David R; Fleck, Robert J et al. (2018) Neonatal Pulmonary Magnetic Resonance Imaging of Bronchopulmonary Dysplasia Predicts Short-Term Clinical Outcomes. Am J Respir Crit Care Med 198:1302-1311|
|Stein, Michelle M; Thompson, Emma E; Schoettler, Nathan et al. (2018) A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol 142:749-764.e3|
|Bønnelykke, Klaus; Coleman, Amaziah T; Evans, Michael D et al. (2018) Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses. Am J Respir Crit Care Med 197:589-594|
|Ober, Carole; Sperling, Anne I; von Mutius, Erika et al. (2017) Immune development and environment: lessons from Amish and Hutterite children. Curr Opin Immunol 48:51-60|
|Hahn, Andrew D; Higano, Nara S; Walkup, Laura L et al. (2017) Pulmonary MRI of neonates in the intensive care unit using 3D ultrashort echo time and a small footprint MRI system. J Magn Reson Imaging 45:463-471|
|Rubner, Frederick J; Jackson, Daniel J; Evans, Michael D et al. (2017) Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence. J Allergy Clin Immunol 139:501-507|
|Turunen, Riitta; Vuorinen, Tytti; Bochkov, Yury et al. (2017) Clinical and Virus Surveillance After the First Wheezing Episode: Special Reference to Rhinovirus A and C Species. Pediatr Infect Dis J 36:539-544|
|Liu, Y-P; Rajamanikham, V; Baron, M et al. (2017) Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes. Clin Exp Allergy 47:371-382|
Showing the most recent 10 out of 157 publications