Neutrophil-mediated inflammatory response is a central component of host defense and also plays a major role in tissue damage as observed in many severe pathophysiological conditions. In studies, we found that PMN undergo phenotypic change during active inflammation and such change is associated with SIRP? alteration in PMN. SIRP? is an essential leukocyte signaling receptor that critically regulates PMN function through extracellular binding interactions with CD47 and intracellular signaling via the immunoreceptor tyrosine-based inhibition motifs (ITIMs). Our hypothesis is that critical inflammatory factors produced at post-acute and chronic stages of inflammation induce deletion of SIRP? ITIMs in PMN resulting in enhanced PMN infiltration and intensified inflammation.
Our specific aims are 1) to determine how SIRP? ITIM deletion enhances PMN-mediated inflammatory response, 2) to determine the role of IL-17 in SIRP? ITIM cleavage and identify the responsible protease in PMN, and 3) to determine the therapeutic potential of functional SIRP? ITIM peptides in suppressing PMN infiltration during chronic inflammation. The goal of this project is to discover novel mechanisms underlying dynamic regulation of inflammation and identify new molecular therapeutic targets for drug design in order to alleviate PMN-mediated inflammatory response especially under chronic inflammation.

Public Health Relevance

This project studies mechanisms that control and regulate inflammation and associated leukocyte function. It also aims to discover new diagnostic and therapeutic methods especially targeting chronic inflammatory diseases, including IBD, infection, cardiovascular disease, diabetes, cancer, etc.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106839-01A1
Application #
8761482
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Nasseri, M Faraz
Project Start
2014-05-20
Project End
2019-04-30
Budget Start
2014-05-20
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$370,000
Indirect Cost
$120,000
Name
Georgia State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302