GLYCOSAMINOGLYCAN-CHEMOKINE INTERACTIONS BY NMR & MASS SPECTROMETRY

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Human chemokines comprise a family of approximately 50 small soluble proteins that interact with about 20 cell surface receptors to regulate cellular migration and signaling events. Many are involved in recruitment and stimulation of immune cells as a part of inflammatory response, but others regulate cell migration during development. While their signaling functions occur through interactions with specific membrane bound G protein-coupled receptors, these interactions are often modulated by interactions with glycosaminoglycans (GAGs). The latter interactions are also believed to be important in the maintenance of gradients of chemokine concentrations necessary for directing the migration of cells to their sites of action, and for the assisted movement of chemokines from the tissue to the luminal side of vascular endothelial layers. The specific targets for this investigation are CCL2 and CCL7. These chemokines are involved in recruitment of monocytes and macrophages in normal physiological processes as well as several diseases. For example, CCL2 recruits CCR2 expressing monocytes into damaged arterial vessels, which then become resident foam cells that promote the development of atherosclerosis. CCL2 also plays a role in cancer. Many tumor cells produce CCL2 to recruit "tumor-associated macrophages" (TAMs) that shape the microenvironment to a state conducive to tumor growth by suppressing the adaptive immune response, and by promoting angiogenesis and metastasis. The Resource is using the NMR and MS methodology it has developed for the CCL5 system to investigate the interaction of CCL2 and CCL7 with various GAG oligomers.