Atopic dermatitis, asthma, and other allergic diseases pose an enormous socioeconomic burden in the United States and worldwide. Current treatment options for these illnesses are, however, limited in efficacy and lead to symptomatic relief in only subsets of patients. More broadly effective therapies against allergic diseases are desperately needed, yet achieving this imperative requires an advanced understanding of their pathogenic mechanisms and identification of new therapeutic targets. The protein kinase p38? is expressed in most mammalian cell types, and activated by a multitude of immunological signals such as microbial stimuli and cytokines. We have been studying the role of p38? in immunity and inflammation using mice with p38? gene deficiency in various cell types. These efforts led us to discover that p38? in skin epithelial cells played a crucial role in driving atopic dermatitis-like inflammation upon allergen challenge. p38? signaling was found to serve pro-allergic functions via promoting the expression of inflammatory mediators in epithelial cells. We identified the matrix metalloproteinase MMP13 as an epithelial enzyme whose expression was dependent on p38? signaling. Importantly, genetic ablation or pharmacological inhibition of MMP13 suppressed allergic skin and airway inflammation in mice. These findings and other preliminary data suggested the p38?-MMP13 axis as a promising therapeutic target for allergic diseases. In the proposed research, we will seek to validate the importance of the p38?-MMP13 axis in allergen-specific immune sensitization and allergic tissue inflammation. Further, we will perform biochemical analysis of cultured cells and recombinant proteins to establish the molecular pathways underlying p38?-dependent MMP13 expression and MMP13-mediated inflammatory responses. To achieve these goals, we will pursue the following specific aims: to determine the role of epithelial p38? signaling and MMP13 activity in mouse models of atopic dermatitis and asthma (Aim #1); to elucidate the mechanisms linking p38? signaling to MMP13 expression in skin and airway epithelial cells (Aim #2); and to identify the proteolytic targets of MMP13 that contribute to regulating allergic inflammation (Aim #3). The proposed research is expected to reveal the precise pathophysiological functions of p38? and MMP13 during allergic inflammation and the therapeutic potential of targeting the p38?-MMP13 axis in atopic dermatitis and asthma. The molecular mechanisms newly identified in our study will expand the sphere of knowledge about cell signaling in allergic disorders.

Public Health Relevance

Complex chemical signals within cells and tissues regulate the working of the immune system. We will investigate whether we can suppress atopic dermatitis and asthma by modulating such signals. Our study aims to generate knowledge and resources that help devise new methods to prevent and treat allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI127768-03
Application #
9589459
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Minnicozzi, Michael
Project Start
2016-11-22
Project End
2021-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114