Project Details
Description
PROJECT SUMMARY
More than 1.5 billion people are infected with helminths worldwide, predominantly distributed in tropical and
subtropical areas. On the other hand, in developed countries with markedly reduced infectious diseases, there
is a continuing increase in the incidences of allergic, inflammatory, and autoimmune diseases. The hygiene
hypothesis proposes that an under-stimulated immune system resulting from the absence of exposure to
helminths, predisposes to autoimmune and allergic inflammation. There is an urgent need for new preventive
and therapeutic medicines for mucosal infection and inflammation. The research in my laboratory has been
focused on the pathophysiological role of O-linked N-Acetylglucosamine (O-GlcNAc) modification on intracellular
proteins at serine and threonine residues. The long-term goal is to elucidate the regulatory mechanisms and
physiological functions of O-GlcNAc signaling in intestinal homeostasis and mucosal host defense. In the
proposed study, we will test the hypothesis that O-GlcNAc transferase (OGT), by activating STAT6 signaling,
promotes the differentiation of IL-25-producing tuft cells and facilitates IL-33 secretion from goblet cells, thus
evoking type 2 immune responses for tissue repair and inflammation control. In Aim 1, we seek to define the
functional impact, upstream activating signals, and downstream targets of STAT6 O-GlcNAcylation in tuft cell
differentiation, type 2 immune activation, and helminth expulsion. In Aim 2, we identify a novel, common target
of OGT and STAT6 that colocalizes with IL-33 in goblet cells and mediates the unconventional secretion of IL-
33 to initiate type 2 immune responses. In Aim 3, using pharmacological and genetic approaches to increase
global protein O-GlcNAcylation in the intestinal epithelium, we expect to establish that the OGT-STAT6 pathway
is required for intestinal homeostasis and mediates the therapeutic effect of helminths in colitis. The proposed
study will provide valuable insights into the development of new intervention strategies to eradicate parasitic
worms in areas of poverty in the developing world and to treat inflammatory bowel disease in industrialized
countries.
Status | Active |
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Effective start/end date | 2/23/22 → 1/31/25 |
Funding
- National Institute of Allergy and Infectious Diseases: $439,561.00
- National Institute of Allergy and Infectious Diseases: $488,402.00
- National Institute of Allergy and Infectious Diseases: $488,402.00
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