Functional Studies of Chemokine and Their Receptors

We complement structural biology experiments with studies using a strain of S. cerevisiae altered to express functional chemokine receptors that are activated by specific chemokines. This strain has been used in high throughput screening of small molecule libraries and the identification of allosteric peptide agonists. It will also be used to create structure-based mutants once the structure of a chemokine-receptor complex is determined.

We are also interested in the role of chemokines and chemokine receptors in disease. We are using a mouse with mutations identical to human mutations that lead to cancer for both mice and humans. We are genetically testing a receptor using a tamoxifen-induced Cre-lox knockout to determine whether the chemokine receptor is involved in the development of cancer in this mouse model or is a potential therapeutic.

We used 168,000 variants of a chemokine in a phage display assay to identify 98 antagonists to its chemokine receptor. We will use high throughput screening to identify the most potent antagonist for in vivo studies with a mouse model of cancer and a mouse model of autoimmune diseases.