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 #
5R01AI106839-04
Application #
9264489
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Lapham, Cheryl K
Project Start
2014-05-20
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
4
Fiscal Year
2017
Total Cost
$423,031
Indirect Cost
$138,027
Name
Georgia State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Bian, Zhen; Shi, Lei; Venkataramani, Mahathi et al. (2018) Tumor conditions induce bone marrow expansion of granulocytic, but not monocytic, immunosuppressive leukocytes with increased CXCR2 expression in mice. Eur J Immunol 48:532-542
Wang, Dong; Sun, Xinlei; Wei, Yao et al. (2018) Nuclear miR-122 directly regulates the biogenesis of cell survival oncomiR miR-21 at the posttranscriptional level. Nucleic Acids Res 46:2012-2029
Bian, Zhen; Abdelaal, Ahmed Mansour; Shi, Lei et al. (2018) Arginase-1 is neither constitutively expressed in nor required for myeloid-derived suppressor cell-mediated inhibition of T-cell proliferation. Eur J Immunol 48:1046-1058
Wei, Yao; Wang, Dong; Jin, Fangfang et al. (2017) Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat Commun 8:14041
Ghimire, Hemendra; Venkataramani, Mahathi; Bian, Zhen et al. (2017) ATR-FTIR spectral discrimination between normal and tumorous mouse models of lymphoma and melanoma from serum samples. Sci Rep 7:16993
Pan, Chaoyun; Zhu, Dihan; Zhuo, Jianjiang et al. (2016) Role of Signal Regulatory Protein ? in Arsenic Trioxide-induced Promyelocytic Leukemia Cell Apoptosis. Sci Rep 6:23710
Bian, Zhen; Shi, Lei; Guo, Ya-Lan et al. (2016) Cd47-Sirp? interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. Proc Natl Acad Sci U S A 113:E5434-43
Niu, Shuo; Bian, Zhen; Tremblay, Alexandra et al. (2016) Broad Infiltration of Macrophages Leads to a Proinflammatory State in Streptozotocin-Induced Hyperglycemic Mice. J Immunol 197:3293-3301
Lee, Young-Tae; Ko, Eun-Ju; Lee, Youri et al. (2016) CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus. J Virol 90:6746-6758
Zhang, Yinwei; Li, Liangwei; Liu, Yuan et al. (2016) PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis. Wound Repair Regen 24:328-36

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