The goal of the proposed research is to understand at a molecular level, how chemokines and their receptors control cellular migration and activation. These proteins are part of a surveillance system that protects the host from pathogens, abnormal cell growth, and other physiological insults. However, deregulated expression of chemokines or their receptors, and unabated infiltration and activation of cells, can cause cell damage. Thus many inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis and atherosclerosis are caused, at least in part, by chemokines. Chemokine receptors are also exploited by HIV as a means of cell entry. Furthermore, over the past few years it has been recognized that many other clinically important viruses mimic, exploit, or target chemokines and chemokine receptors as a mechanism for suppressing the host immune response. Chemokines and their receptors are therefore now considered attractive targets for the treatment of many human diseases. ? ? In order to understand how these proteins function, we take an approach that combines structural, biophysical, biochemical and in vivo studies. Specifically, our goals are to determine structures of these proteins, understand the molecular details of receptor binding and signaling, understand if, how, and why they bind to cell surface glycosaminoglycans (GAGs), and how viral chemokine proteins manipulate the chemokine system. In parallel with these fundamental studies we attempt to identify protein variants that are receptor antagonists, and therefore potential protein therapeutics or reagents that can be used to investigate the roles of specific receptors and chemokines in disease.
The specific aims of the proposal are as follows: ? ? 1. Investigate the relevance and structural details of the interaction of chemokines with glycosaminoglycans, focusing on the chemokine MCP-1. ? ? 2. Identify specific GAG sequences that are preferentially recognized by chemokines. ? ? 3. Characterize the details of receptor binding, signaling and GAG binding of additional chemokines that bind to the MCP-1 receptor, CCR2. ? ? 4. Conduct a structural survey of chemokines that form higher order oligomers and/or that are oligomerized by GAGs to investigate the functional relevance of oligomerization and the diversity of oligomeric structures. ? ? 5. Characterize the interaction of chemokines with a viral chemokine binding protein. ? ?
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