Office: 540F Bond Life Sciences Center
Mail: Christopher S. Bond Life Sciences Center
540F Bond Life Sciences Center
University of Missouri
Columbia, MO 65211
|BS||Drury College||Springfield, Mo.||Chemistry and Biology|
|MS||University of Missouri||Columbia, Mo.||Biochemistry|
|PhD||University of Missouri||Columbia, Mo.||Biochemistry|
Our general mission is to understand how tissue damage causes the body to mount an inflammatory response. Over the last decade, a new hypothesis of how our bodies respond to tissue damage or pathogenic invasion has taken place. The current prevailing hypothesis is that an inflammatory response does not occur solely in response to foreign or nonself molecules but, rather, in response to self molecules released from damaged tissue. The self molecules responsible for mounting an inflammatory response have not been conclusively identified, although it is speculated that they must have the following features: 1) they should be easily and quickly generated in the extracellular space, probably by release from an existing intracellular pool, 2) under resting conditions their extracellular concentration should be close to zero to allow a high signal-to-noise ratio upon release, 3) they should be highly mobile in the pericellular environment, 4) they should be recognized by specific receptors expressed in immune cells, and 5) they should be easily destroyed once they reach the extracellular space. Since nucleotides meet all these criteria, these molecules and their cell surface receptors (P2 receptors) have emerged as key players in the process of inflammation.
In injured tissue, ATP and other nucleotides are immediately released from damaged cells where they assist in localized platelet aggregation by activating platelet P2Y1 and P2Y12 receptors. Aggregated platelets then release molar quantities of ATP from secretory vesicles, leading to a variety of P2 receptor-mediated inflammatory events, including blood vessel dilation, cytokine release and leukocyte recruitment from the blood to the site of injury. Other sources of extracellular ATP in damaged tissue include hypoxic red blood cells, activated neurons and migrating leukocytes which release bursts of ATP at their leading edge. Although several subtypes of P2 receptors have been reported to mediate pro-inflammatory responses, the P2Y2 receptor subtype (P2Y2R) appears to be unique in its ability to be upregulated in vascular tissue under conditions of stress or injury. By examining P2Y2R function in immune and vascular cells and in in vivo injury models we hope to provide a better understanding of how nucleotides influence inflammation and wound healing.
The P2Y2R, which is normally expressed in monocytes and neutrophils, has been shown to control adhesion of leukocytes to vascular endothelium, an early event in the inflammatory process. Recent studies in our lab have begun to delineate the molecular basis of P2Y2R-mediated monocyte adhesion, chemotaxis and diapedesis or migration of monocytes/leukocytes across the endothelial layer that lines blood vessels. Specifically, we have identified consensus Src-homology-3 (SH3) binding sites in the intracellular C-terminal tail of P2Y2R that bind directly to Src and allow the P2Y2R to co-localize with and transactivate several growth factor receptors, including VEGFR-2 in endothelial cells. Furthermore, we have found that transactivation of VEGFR-2 by the P2Y2R causes upregulation of VCAM-1, a cell adhesion molecule important for monocyte adherence. Other studies in our lab have demonstrated that an integrin-binding domain in the P2Y2R allows this receptor to associate with αVβ3 and αVβ5 integrins, adhesion molecules that are important for both leukocyte migration and angiogenesis. Since the P2Y2R co-localizes with growth factor receptors and also with αVβ3/5 integrins, we speculate that the P2Y2R may be a component of a large signaling complex containing integrins and proteins associated with integrins such as Src, focal adhesion kinase, Pyk2, growth factor receptors, and the actin cytoskeleton. A better understanding of the nature of these multi-protein interactions and signaling events involving P2Y2Rs will likely identify intervention points for selectively controlling P2Y2R activities that mediate inflammatory responses, leading to new treatments for inflammatory disorders, such as atherosclerosis and ulcers.
Seye CI, Kong Q, Yu N, Gonzalez FA, Erb L, Weisman GA. 2015. Erratum to: P2 receptors in atherosclerosis and postangioplasty restenosis. Purinergic Signal. 2015 Sep;11(3):409.
Woods LT, Camden JM, El-Sayed FG, Khalafalla MG, Petris MJ, Erb L, Weisman GA. Increased Expression of TGF-β Signaling Components in a Mouse Model of Fibrosis Induced by Submandibular Gland Duct Ligation. PLoS One. 2015 May 8;10(5):e0123641. eCollection 2015.
Liao Z, Cao C, Wang J, Huxley VH, Baker O, Weisman GA, Erb L. The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells. J Biomed Sci Eng. 2014 Dec 1;7(14):1105-1121.
Erb L, Cao C, Ajit D, Weisman GA. P2Y receptors in Alzheimer's disease. Biol Cell. 2015 Jan;107(1):1-21. Epub 2014 Oct 13. Review.
El-Sayed FG, Camden JM, Woods LT, Khalafalla MG, Petris MJ, Erb L, Weisman GA. P2Y2 nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells. Am J Physiol Cell Physiol. 2014 Jul 1;307(1):C83-96. Epub 2014 Apr 23.
Ajit D, Woods LT, Camden JM, Thebeau CN, Greeson GW, Erb L, Petris M, Miller DC, Sun GY and Weisman GA. Loss of P2Y2 Nucleotide Receptors Enhances Early Pathology in TgCRND8 Mouse Model of Alzheimer’s Disease. J. Mol. Neurobiol. 2014; 49: 1031-42.