Psoriasis is a common, chronic, cytokine driven inflammatory and hyper-proliferative skin disease associated with significant cardiovascular and metabolic co-morbidities. Major progress has been made in recent years delineating genetic risk factors predisposing to psoriasis through genome-wide association studies (GWAS), with 41 susceptibility loci identified to date. The clinical importance of these findings is underscored by the fact that several risk loci point to pathways and molecules already targeted for the treatment of psoriasis. More importantly, the GWAS results have the potential to identify previously unappreciated pathways, which may be critical in the disease pathogenesis and therefore ideal therapeutic targets. One of these risk variants is located within the IL13 gene, but the role of IL 13 in psoriasis pathogenesis is mostly unknown. However, several lines of evidence, including our own preliminary data, point towards a major role for IL-13 in psoriasis, setting the stage for our hypothesis that IL-13 has a pro-inflammatory role in the pathogenesis of psoriasis by potentiating Th1 and Th17 induced skin inflammation. The objective of this proposal is to define the pathogenic role of IL-13 in psoriasis, elucidate the critical pathways and mechanisms involved, and assess the impact of the psoriasis-associated IL13 rs20541 risk variant on inflammation in psoriatic skin. This project will provide new data on an unappreciated and understudied inflammatory pathway in the pathogenesis of psoriasis, it will assess the potential of targeting IL-13 or its receptor system in psoriasis, and ultimately lead the way towards more effective treatments for patients with this chronic, and often, devastating disease.

Public Health Relevance

Major progress has been made in recent years in delineating the genetic variants that predispose to psoriasis. The importance of these findings is that these genetic variants can point towards previously unappreciated pathways that are critical in the disease pathogenesis, and therefore can lead to development of novel treatments. The objective of this proposal is to define the pathogenic role of IL-13 in psoriasis, elucidate the mechanism by which IL-13 contribute to disease development, and assess the impact of the psoriasis- associated IL13 variant on psoriasis inflammatory responses. The impact of this work is that it will provide new data on an unappreciated and understudied inflammatory pathway in the pathogenesis of psoriasis, it can lead to identification of a novel therapeutic target in psoriasis, and ultimately to more effective treatment for patients with this chronic, and often, devastating disease

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR069071-01
Application #
9008122
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (02))
Program Officer
Cibotti, Ricardo
Project Start
2015-09-16
Project End
2020-07-31
Budget Start
2015-09-16
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$442,353
Indirect Cost
$119,487
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Swindell, William R; Michaels, Kellie A; Sutter, Andrew J et al. (2017) Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis. Genome Med 9:24
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