Access Type

Open Access Thesis

Date of Award

January 2012

Degree Type

Thesis

Degree Name

M.S.

Department

Biochemistry and Molecular Biology

First Advisor

Chunying Li

Abstract

Neutrophils are the body's first responders to inflammation, being the most abundant white blood cell type in circulation and they quickly initiate an immune response through chemokine signaling. Inflammatory chemokines signal via their receptor CXCR2, which initiates an inflammatory response, recruiting leukocytes to sites of inflammation. Chemokine signaling is important for proper host protection, yet uncontrolled activity is responsible for a variety of pathological conditions: including rheumatoid arthritis, ischemia-reperfusion injury, arteriosclerosis, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergic reactions.

In this report I show a CXCR2 macromolecular signaling complex exists in neutrophils, containing NHERF1 and PLCĪ²2. I also demonstrate a novel strategy of cytosolically perturbing the CXCR2 PDZ-domain interaction of the macromolecular complex. This perturbation disrupts spatial sensation of a chemokine gradient, yet still allows cells to mobilize actin and chemotax. Furthermore, I show CXCR2 PDZ-domain perturbation does not disrupt migration through bacterial derived chemoattractant receptors.

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