Chemoattractant cytokines or chemokines are small, secreted proteins that activate leukocytes. Aberrant chemokine responses contribute to inflammatory diseases such as asthma and atherosclerosis. A growing body of evidence implicates the PI3-kinase (PI3-K) pathway as a critical mediator of chemokine signaling in leukocytes. Our preliminary data suggest that both chemokines and PI3-kinase potently activate Integrin Linked Kinase (ILK) in leukocytes, and that this has important functional consequences. ILK is a 59 kDa serine/threonine kinase, that also interacts with both beta integrins and actin binding proteins. Based on in vitro studies utilizing gene transfer in human leukocyte cell lines, as well as genetically engineered ILK-deficient murine leukocytes, we hypothesize that ILK serves as a counter-regulatory, negative modulator of adhesion that facilitates subsequent transendothelial migration and chemotaxis. We further hypothesize that these functions are dependent on ILK kinase activity and will result in abnormalities of in vivo trafficking in inflammatory models. To test these hypotheses, we will utilize murine models of leukocyte-specific ILK deletion and gene transfer in combination with in vitro and in vivo models of leukocyte trafficking and inflammation.
In Specific Aim 1, we will assess the functional effects of ILK deficiency on leukocyte recruitment in chemotaxis and adhesion assays in vitro.
In Specific Aim 2, we will define the downstream mechanisms by which ILK modulates leukocyte chemotaxis and adhesion.
In Specific Aim 3, we will test whether the in vitro functional effects observed in ILKdeficient leukocytes are recapitulated in inflammatory models in vivo. Understanding the role of specific signaling pathways in leukocyte recruitment may provide new targets for the management of many inflammatory disorders.
| Shen, Dongxiao; Li, Jian; Lepore, John J et al. (2011) Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells. Circ Res 109:616-28 |
| Kristo, Fjoralba; Hardy, Gregory J; Anderson, Thomas J T et al. (2010) Pharmacological inhibition of BLT1 diminishes early abdominal aneurysm formation. Atherosclerosis 210:107-13 |
| Barth, Marita C; Ahluwalia, Neil; Anderson, Thomas J T et al. (2009) Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. J Biol Chem 284:19189-95 |
| King, Victoria L; Lin, Alexander Y; Kristo, Fjoralba et al. (2009) Interferon-gamma and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture. Circulation 119:426-35 |
| Dandapani, Savita V; Sugimoto, Hikaru; Matthews, Benjamin D et al. (2007) Alpha-actinin-4 is required for normal podocyte adhesion. J Biol Chem 282:467-77 |
| Shinde Patil, Vivek R; Friedrich, Erik B; Wolley, Allison E et al. (2005) Bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells do not contribute to vasculogenesis in Lewis lung carcinoma. Neoplasia 7:234-40 |
| Tager, Andrew M; Bromley, Shannon K; Medoff, Benjamin D et al. (2003) Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol 4:982-90 |
| Kos, Claudine H; Le, Tu Cam; Sinha, Sumita et al. (2003) Mice deficient in alpha-actinin-4 have severe glomerular disease. J Clin Invest 111:1683-90 |
| Friedrich, Erik B; Sinha, Sumita; Li, Ling et al. (2002) Role of integrin-linked kinase in leukocyte recruitment. J Biol Chem 277:16371-5 |
| Meiler, Steffen E; Hung, Rebecca R; Gerszten, Robert E et al. (2002) Endothelial IKK beta signaling is required for monocyte adhesion under laminar flow conditions. J Mol Cell Cardiol 34:349-59 |
Showing the most recent 10 out of 11 publications
