Our long-term goal is to study the mechanisms of protein ubiquitination in the regulation of immune responses. Allergic asthma is a chronic inflammatory disease of the airways featured by the elevated serum immunoglogulin E (IgE) concentrations, airway hyperresponsiveness, excessive airway mucus production, lung eosinophilia, and airway remodeling. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce Th2 type cytokines to drive asthmatic pathogenesis. The Th2-mediated immune responses are counterbalanced by tolerogenic mechanisms that keep the excessive reaction under control. One of the tolerance mechanisms involves regulatory T cells (Tregs) that limit the allergic responses. Transforming growth factor (TGF)-? is critically involved in the generation and function of Tregs. Using both in vivo and in vitro model systems, we recently obtained preliminary data suggesting that the E3 ubiquitin ligase Itch plays an important role in the TGF-?-induced expression of Foxp3 and Treg- mediated proliferative inhibition. The new preliminary data allow us to formulate a hypothesis that the E3 ubiquitin ligase Itch is an important regulator in TGF-? signaling, which is linked to TGF-?-induced Treg generation. Such regulation of T cell function underlies the mechanistic involvement of Itch in the development of Th2-mediated allergic responses. We plan to test this hypothesis by proposing detailed experiments to elucidate the intracellular signaling pathways modulated by Itch-induced protein ubiquitination, with a combination of both genetic and biochemical approaches. Such studies will help to design novel therapeutic interventions for allergic diseases.

Public Health Relevance

Mechanisms of protein ubiquitination in regulating airway inflammation Narrative Asthma is on the rise in both industrialized and developing countries, which affects over 20 million people in the US alone. Allergic asthma is a chronic inflammatory disease of the airways. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce cytokines, which are critical to drive asthmatic pathogenesis. This proposal is to study the regulatory mechanisms to control excessive T cell activation. The knowledge gained from the proposed research will help design new therapeutic approaches for human allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078272-05
Application #
8389645
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Dong, Gang
Project Start
2008-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$379,344
Indirect Cost
$172,052
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Liu, Yun-Cai (2007) The E3 ubiquitin ligase Itch in T cell activation, differentiation, and tolerance. Semin Immunol 19:197-205