Objective: The overall goal of this proposal is to test the hypothesis that during allergic airway inflammation, epicutaneous sensitization induces Thymic Stromal Lymphopoeitin (TSLP), a cytokine biomarker for skin barrier defects, which then regulates the recruitment and function of free radical producing-airway myeloid - derived regulatory cells (MDRC), that are critical modulators of airway hyper-responsiveness (AHR). The proposed studies may uncover mechanisms linking MDRC and progression of atopic dermatitis to allergic rhinitis to asthma, the concept called 'atopic march'.
Specific Aims : (1) To test the hypothesis that route of allergen sensitization modulates the recruitment of airway MDRC during allergic airway inflammation via free radical dependent mechanisms (2)To determine whether increase in skin-derived or systemic TSLP levels regulates the activation and/or recruitment of 0 2 . - producing MDRC into allergic airway s and promotes AHR Research Design: Epicutaneous or intraperitoneal sensitization followed by intranasal challenge with ovalbumin induces allergic airway inflammation in the mouse model proposed in this study. MDRC will be analyzed and purified from bronchoalveolar lavage, lung tissue and secondary lymphoid organs at different time points following intranasal antigen challenge to determine their recruitment and function. Genetic knockouts and pharmacologic inhibitors of free radical pathways will be utiized to assess the free-radical mediated regulation of recruitment of MDRC and their potential to control T cell responses and AHR (measured by flexivent). The role of TSLP in modulating recruitment and function of MDRC will be delineated using anti-TSLP antibodies in conjunction with transgenic mice constitutively expressing TSLP. Rationale: Sub populations of NO- and 02.-producing mouse lung MDRC are master regulators of allergic airway inflammation. NO-producing MDRC suppress while 02.-producing MDRC enhances T cell responses and airway hyper-responsiveness. A balance in the ratio of immunosupressive and proinflammatory MDRC is critical for the control of inflammation. Recent studies indicate that high systemic levels of skin-derived TSLP is sufficient to render airway s hypersensitive to allergens. Studies to date have not investigated the potential role of TSLP in regulating the activation and/or recruitment of MDRC into allergic airway s. This study proposes a novel role for MDRC in understanding the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.

Public Health Relevance

70% of patients with history of severe AD develop allergic asthma, a phenomenon referred to as atopic march. Understanding the underlying mechanisms could help develop strategies for early treatment of skin barrier defects and block the progression of atopic march in these patients. We propose a novel role for MDRC in the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
5P30AR050948-09
Application #
8524199
Study Section
Special Emphasis Panel (ZAR1-KM-D (M1))
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$40,800
Indirect Cost
$12,950
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Garcia, S S; Blackledge, M S; Michalek, S et al. (2017) Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome. J Dent Res 96:807-814
Paulsen, Jesseca A; Ptacek, Travis S; Carter, Stephen J et al. (2017) Gut microbiota composition associated with alterations in cardiorespiratory fitness and psychosocial outcomes among breast cancer survivors. Support Care Cancer 25:1563-1570
Brawner, K M; Kumar, R; Serrano, C A et al. (2017) Helicobacter pylori infection is associated with an altered gastric microbiota in children. Mucosal Immunol 10:1169-1177
Larson, Thomas R; Yother, Janet (2017) Streptococcus pneumoniae capsular polysaccharide is linked to peptidoglycan via a direct glycosidic bond to ?-D-N-acetylglucosamine. Proc Natl Acad Sci U S A 114:5695-5700
Kim, T; Holleman, C L; Ptacek, T et al. (2017) Duodenal endoluminal barrier sleeve alters gut microbiota of ZDF rats. Int J Obes (Lond) 41:381-389
Childers, Noel K; Grenett, Hernan; Morrow, Casey et al. (2017) Potential Risk for Localized Aggressive Periodontitis in African American Preadolescent Children. Pediatr Dent 39:294-298
Nasti, Tahseen H; Cochran, J Barry; Vachhani, Raj V et al. (2017) IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations. J Immunol 198:950-961
Demark-Wahnefried, Wendy; Nix, Jeffery W; Hunter, Gary R et al. (2016) Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a wait-list control on tumor characteristics and circulating biomarkers in men electing prostatectomy for BMC Cancer 16:61
Frugé, Andrew D; Ptacek, Travis; Tsuruta, Yuko et al. (2016) Dietary Changes Impact the Gut Microbe Composition in Overweight and Obese Men with Prostate Cancer Undergoing Radical Prostatectomy. J Acad Nutr Diet :
Edwards, Rodney K; Kumar, Ranjit; Zhi, Degui et al. (2016) Gravidas with class III obesity: evaluating the abdominal skin microbiota above and below the panniculus (.). J Matern Fetal Neonatal Med 29:3312-6

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