Fractalkine, a newly cloned CX3C chemokine, is an endothelium-derived lymphoctye and macrophage chemoattractant, and is unique as the only chemokine mounted on a mucin stalk and having a transmembrane domain. This structure may optimize its function in high-flow vascular circuits such as the renal glomerulus. The Principal Investigator has shown that a neutralizing antibody (Ab) against the receptor for fractalkine, CX3CR1, almost completely prevented CD8+ lymphocyte-dependent and monocyte/macrophage-related anti-glomerular basement membrane (GBM) Ab-induced glomerulonephritis (GN) in the Wistar-Kyoto (WKY) rat. This suggests that the fractalkine/CX3CR1 ligand/receptor pair play a central role in immune-mediated inflammation in the glomerulus. The Principal Investigator proposes to explore the mechanisms of fractalkine regulation and signaling in glomerular endothelial cells (GenC), as well as how fractalkine-expressing GenC cross-communicate with CX3CR1-bearing cells, mainly monocytes/macrophages. The Principal Investigator will study when fractalkine can be induced, what fractalkine can regulate, and how fractalkine can function. The Principal Investigator will, by dissecting the individual domains of fractalkine (including its chemokine, mucin, transmembrane, and cytoplasmic domains), study the role of the molecule in fractalkine-mediated cellular events, including chemotaxis, cell adhesion, activation of macrophage proliferation in vitro in GenC and in vivo in renal inflammation. The Principal Investigator will continue to develop a fractalkine antagonist for better in-depth understanding of the relationship between the structure and activity of the molecule, which in addition will provide insightful information for drug design. Finally, the Principal Investigator will use the antagonist, along with other chemokine antagonist controls and blockers, to determine the in vivo effects of fractalkine on acute inflammation and also on the proliferation of monocytes/macrophages as they contribute to continued injury and destruction in experimental glomerular and tubulointestinal renal injury. The Principal Investigator believes that these studies will provide new drug targets for many human disorders that may be fractalkine/CX3CR1-associated, including GN, vasculitis, allograft rejection, ischemia/reperfusion injury, thrombotic angiopathies, and atherosclerosis.
| Li, Ping; Garcia, Gabriela E; Xia, Yiyang et al. (2005) Blocking of monocyte chemoattractant protein-1 during tubulointerstitial nephritis resulted in delayed neutrophil clearance. Am J Pathol 167:637-49 |
| Kanellis, John; Garcia, Gabriela E; Li, Ping et al. (2004) Modulation of inflammation by slit protein in vivo in experimental crescentic glomerulonephritis. Am J Pathol 165:341-52 |
