Structure-Function Studies of Chemokines and Receptors

描述（由申请人提供）：拟议研究的目标是在分子水平上了解趋化因子及其受体如何控制细胞迁移和激活。这些蛋白质是监视系统的一部分，保护宿主免受病原体、异常细胞生长和其他生理损伤。然而，趋化因子或其受体的表达失调，以及细胞的浸润和活化不减弱，可导致细胞损伤。因此，许多炎症性疾病，如类风湿关节炎、哮喘、多发性硬化症和动脉粥样硬化，至少部分是由趋化因子引起的。趋化因子受体也被HIV利用作为进入细胞的手段。此外，在过去的几年里，人们已经认识到许多其他临床上重要的病毒模仿、利用或靶向趋化因子和趋化因子受体作为抑制宿主免疫反应的机制。因此，趋化因子及其受体现在被认为是治疗许多人类疾病的有吸引力的靶点。

DESCRIPTION (provided by applicant): 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.