A major goal of the this AADCRC program is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and develop new preventative strategies. In that context, this project aims to investigate means by which to block progression from atopic dermatitis to asthma (often referred to as the atopic march). Patients with a history of severe atopic dermatitis (AD) exhibit a 8-to-10-fold greater incidence of developing asthma. Our recent observations demonstrated that in mice, epidermal-derived thymic stromal lymphopoietin (TSLP) was secreted by AD skin. Moreover, circulating levels of TSLP were sufficient to sensitize the lung airways to inhaled allergens in animals lacking any AD-like pathology, preexisting inflammation, or previous exposure to the allergen. In a pilot study in infants we uncovered a correlation between serum TSLP and aeroallergens. Based on these observations in mice and humans, we hypothesize the following mechanism for the atopic march. (1) Epidermal defect/injury during early childhood is sensed by an unknown mechanism that initiates production of TSLP in keratinocytes;(2) keratinocytes secrete TSLP into the serum. (3) Subsequently, circulating TSLP facilitates Th2 immune responses by dendritic cells and T-cells towards innocuous allergens (inhaled or introduced epicutaneously);and (4) this exaggerated adaptive Th2 response results in hypersensitivity to aeroallergens and consequent allergic asthma. We further hypothesize that interrupting some of these events in a model organism will lead to strategies for blocking the development of allergic disease and asthma in humans. To achieve this goal, we propose the to (I) examine how epidermal differentiation/barrier formation defects (intrinsic factors) as well as allergen or pathogens (extrinsic factor(s)) drive TSLP overexpression;(II) with the help of Cores B and C ask how TSLP secretion is regulated by human skin and lung cells in vitro and in patients. Next, (III) we will ask if we can blunt the effects of TSLP in the serum with small molecule adjuvants capable of manipulating the immune responses and (IV) analyze the contribution of the skin microbiome to the maintenance of skin barrier, TSLP expression, and airway hyper sensitivity. Finally, (V) we will confirm TSLP as a risk factor for asthma in a birth cohort (URECA) and, in collaboration with project1, compare its role in an RSV bronchiolitis in early life cohort (RBEL). Achievement of these aims will open up novel therapeutic approach to prevent asthma development in AD patients.
A preexisting skin condition in children is a strong risk factor for asthma in adulthood. This proposal aims directly at the mechanism linking hose allergic conditions issue by defining the elements controlling expression, secretion and function of TSLP, a secreted cytokine we show can explain the atopic march. At minimum, we expect to provide strategies that will help prevent atopic march in at-risk AD patients. In the best case scenario, we may uncover novel pathways to therapeutic intervention.
|Demehri, S; Yockey, L J; Visness, C M et al. (2014) Circulating TSLP associates with decreased wheezing in non-atopic preschool children: data from the URECA birth cohort. Clin Exp Allergy 44:851-7|
|Gu, Xiaoling; Karp, Philip H; Brody, Steven L et al. (2014) Chemosensory functions for pulmonary neuroendocrine cells. Am J Respir Cell Mol Biol 50:637-46|
|Patel, Dhara A; Patel, Anand C; Nolan, William C et al. (2014) High-throughput screening normalized to biological response: application to antiviral drug discovery. J Biomol Screen 19:119-30|
|Xu, Wei; Edwards, Megan R; Borek, Dominika M et al. (2014) Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16:187-200|
|Patel, Dhara A; You, Yingjian; Huang, Guangming et al. (2014) Interferon response and respiratory virus control are preserved in bronchial epithelial cells in asthma. J Allergy Clin Immunol 134:1402-1412.e7|
|Pennati, Francesca; Quirk, James D; Yablonskiy, Dmitriy A et al. (2014) Assessment of regional lung function with multivolume (1)H MR imaging in health and obstructive lung disease: comparison with (3)He MR imaging. Radiology 273:580-90|
|Kober, Daniel L; Wanhainen, Kelsey M; Johnson, Britney M et al. (2014) Preparation, crystallization, and preliminary crystallographic analysis of wild-type and mutant human TREM-2 ectodomains linked to neurodegenerative and inflammatory diseases. Protein Expr Purif 96:32-8|
|Pan, Jie-Hong; Adair-Kirk, Tracy L; Patel, Anand C et al. (2014) Myb permits multilineage airway epithelial cell differentiation. Stem Cells 32:3245-56|
|Holtzman, Michael J; Byers, Derek E; Alexander-Brett, Jennifer et al. (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686-98|
|Philippot, Quentin; Deslée, Gaëtan; Adair-Kirk, Tracy L et al. (2014) Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. PLoS One 9:e96285|
Showing the most recent 10 out of 29 publications