Skin inflammation in Atopic Dermatitis (AD) patients includes dendritic cells, mast cells and T cells. Evidence for the function of several T helper subsets in AD exists both from patient samples and from mouse models. There is clearly a genetic component in disease;family history of allergy is one of the strongest predictors of AD, and mutations in the filaggrin (FLG) gene, a component of the Epidermal Differentiation Complex (EDC), have emerged as a predisposing factor for the development of AD. IL-4 and IL-13 promote atopic responses and decrease expression of a number of EDC genes, which are critical for barrier function. One of the primary questions that remain unanswered is whether the defect leading to AD is in the skin, in the atopic immune system, or whether disease requires defects in both systems. Central to answering this question is an understanding of how the immune system and the skin, particularly keratinocytes, interact at the molecular level. The overall goal of this Project is to define the interactions of cytokines that promote the development of atopic inflammation on keratinocyte gene expression and function, with the long-term goal of finding pathways that could be targeted for treatment of disease. Our hypothesis is that pro-allergic cytokines change the biology of keratinocytes and alter barrier function, facilitating increased allergen exposure. This hypothesis will be examined in two Aims that will examine the interactions of filaggrin mutations with increased Th2 immunity in a mouse model system, and define the function of STAT6 in regulating keratinocyte gene expression. Together, these studies will provide a detailed understanding of the effects of cytokines produced during allergic inflammation on skin barrier function.

Public Health Relevance

Skin provides a barrier to harmful components in the environment including infection. Atopic Dermatitis, an allergic disease of the skin alters the barrier function of the skin and increases allergic inflammation and infection. This proposal defines the mechanism of altered barrier function and examines the interactions of the immune system with genes involved in barrier function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095282-02
Application #
8420261
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Minnicozzi, Michael
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$366,600
Indirect Cost
$131,600
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Krishnamurthy, Purna; Sherrill, Joseph D; Parashette, Kalyan et al. (2014) Correlation of increased PARP14 and CCL26 expression in biopsies from children with eosinophilic esophagitis. J Allergy Clin Immunol 133:577-80
Walline, Crystal C; Sehra, Sarita; Fisher, Amanda J et al. (2013) Allergic airway disease in mice alters T and B cell responses during an acute respiratory poxvirus infection. PLoS One 8:e62222
Kaplan, Mark H; Cundiff, Judy K; Smith, Jill Stader et al. (2013) Anti-STAT6 CTL activity in Stat6 (-/-) mice: A cautionary tale. JAKSTAT 2:e24554
Turner, Matthew J; Dasilva-Arnold, Sonia C; Yi, Qiaofang et al. (2013) Topical application of a vitamin D analogue exacerbates atopic dermatitis and induces the atopic dermatitis-like phenotype in Stat6VT mice. Pediatr Dermatol 30:574-8
Handlogten, Michael W; Kiziltepe, Tanyel; Serezani, Ana P et al. (2013) Inhibition of weak-affinity epitope-IgE interactions prevents mast cell degranulation. Nat Chem Biol 9:789-95