Klaus Ley
Primary Appointment
, Biomedical Engineering
Research Description
1. Leukocyte recruitment and proliferation in inflammation
2. Monocyte adhesion in atherosclerosis and diabetes
3. Molecular mechanisms of inflammation in Crohn's disease
4. Biomechanics of leukocyte adhesion
5. Adhesion molecule and chemokine knockout mice
6. Targeted contrast agents for ultrasound and MRI
7. Cardiovascular MRI, specifically in mouse models
8. Cardiovascular genomics
9. Cardiovascular biomarker discovery program
Techniques in Use
1. Intravital microscopy of transgenic and knockout mice
2. Cell culture of various transfectants, isolation of primary blood cells mouse and human
3. Flow cytometry
4. Immunostaining for adhesion molecules and chemokines
5. Isolated-perfused mouse carotid artery
6. Bone marrow transplantation
Current Summary
Inflammatory cell recruitment requires the concerted action of at least four major sets of adhesion molecules: integrins, immunoglobulin-like molecules, selectins, and carbohydrate structures serving as selectin ligands. Selectin-mediated adhesion represents the first step in the cascade required for leukocyte recruitment. The three known selectins (E-, L- and P-selectin) have been shown to be involved in mediating leukocyte rolling, which is a transient adhesion event during early inflammation. My laboratory investigates the involvement of the selectins in initial leukocyte attachment and emigration in vivo, mainly by using the method of intravital microscopy. We use blocking monoclonal antibodies, cell lines transfected with selectin molecules and selectin-deficient mice made by gene targeting and homologous recombination. Inflammation is experimentally induced by tissue trauma and/or injection of the pro-inflammatory cytokine TNF-alpha.
Atherosclerotic lesions develop and progress through recruitment of monocytes into the arterial wall. This process appears to also involve adhesion molecules. Preliminary data suggest that P-selectin, L-selectin, and the immunoglobulin-like molecule VCAM-1 may be involved in monocyte recruitment into atherosclerotic lesions. We use an isolated perfused mouse carotid artery to study adhesion of monocytes and monocyte-like cell lines with the aim of identifying the relevant molecular mechanisms. The mouse model is useful because gene-targeted mice lacking apolipoprotein E (apoE) are available which develop atherosclerotic lesions.
The results of this research are expected to augment the basic understanding of the inflammatory process as well as the potential for developing anti- inflammatory and anti-atherogenic therapies for future clinical use in patients.
Selected Publications
Morris MA, McDuffie M, Nadler JL, Ley K, Prevention, but not cure, of autoimmune diabetes in a NOD.scid transfer model by FTY720 despite effective modulation of blood T cells., 2010; Autoimmunity. 0(0) null.
Reutershan J, Saprito MS, Wu D, Rückle T, Ley K, Phosphoinositide 3-kinase gamma required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung., 2010; Eur Respir J. 35(5) 1137-47.
Ferrante EA, Pickard JE, Rychak J, Klibanov A, Ley K, Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow., 2009; J Control Release. 140(2) 100-7.
Smith E, von S, Stark MA, Zarbock A, Sanders JM, Duley A, Rivera-Nieves J, Bender TP, Ley K, T-lineage cells require the thymus but not VDJ recombination to produce IL-17A and regulate granulopoiesis in vivo., 2009; J Immunol. 183(9) 5685-93.
Harry BL, Sanders JM, Feaver RE, Lansey M, Deem TL, Zarbock A, Bruce AC, Pryor AW, Gelfand BD, Blackman BR, Schwartz MA, Ley K, Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice., 2008; Arterioscler Thromb Vasc Biol. 28(11) 2003-8.
Zarbock A, Abram CL, Hundt M, Altman A, Lowell CA, Ley K, PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling., 2008; J Exp Med. 205(10) 2339-47.
Smith E, Stark MA, Zarbock A, Burcin TL, Bruce AC, Vaswani D, Foley P, Ley K, IL-17A inhibits the expansion of IL-17A-producing T cells in mice through "short-loop" inhibition via IL-17 receptor., 2008; J Immunol. 181(2) 1357-64.
Li G, Sanders JM, Bevard MH, Sun Z, Chumley JW, Galkina EV, Ley K, Sarembock IJ, CD40 ligand promotes Mac-1 expression, leukocyte recruitment, and neointima formation after vascular injury., 2008; Am J Pathol. 172(4) 1141-52.
Zarbock A, Ley K, Mechanisms and consequences of neutrophil interaction with the endothelium., 2008; Am J Pathol. 172(1) 1-7.
Rychak JJ, Klibanov AL, Ley KF, Hossack JA, Enhanced targeting of ultrasound contrast agents using acoustic radiation force., 2007; Ultrasound Med Biol. 33(7) 1132-9.
Smith E, Zarbock A, Stark MA, Burcin TL, Bruce AC, Foley P, Ley K, IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice., 2007; J Immunol. 179(12) 8274-9.
Zarbock A, Deem TL, Burcin TL, Ley K, Galphai2 is required for chemokine-induced neutrophil arrest., 2007; Blood. 110(10) 3773-9.
Ley K, Laudanna C, Cybulsky MI, Nourshargh S, Getting to the site of inflammation: the leukocyte adhesion cascade updated., 2007; Nat Rev Immunol. 7(9) 678-89.
Reutershan J, Cagnina RE, Chang D, Linden J, Ley K, Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury., 2007; J Immunol. 179(2) 1254-63.
Zarbock A, Lowell CA, Ley K, Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1., 2007; Immunity. 26(6) 773-83.
Stockton R, Reutershan J, Scott D, Sanders J, Ley K, Schwartz MA, Induction of vascular permeability: beta PIX and GIT1 scaffold the activation of extracellular signal-regulated kinase by PAK., 2007; Mol Biol Cell. 18(6) 2346-55.
Reutershan J, Stockton R, Zarbock A, Sullivan GW, Chang D, Scott D, Schwartz MA, Ley K, Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear leukocyte infiltration., 2007; Am J Respir Crit Care Med. 175(10) 1027-35.
Cho HJ, Shashkin P, Gleissner CA, Dunson D, Jain N, Lee JK, Miller Y, Ley K, Induction of dendritic cell-like phenotype in macrophages during foam cell formation., 2007; Physiol Genomics. 29(2) 149-60.
Klibanov AL, Rychak JJ, Yang WC, Alikhani S, Li B, Acton S, Lindner JR, Ley K, Kaul S, Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow., 2006; Contrast Media Mol Imaging. 1(6) 259-66.
Smith DF, Deem TL, Bruce AC, Reutershan J, Wu D, Ley K, Leukocyte phosphoinositide-3 kinase {gamma} is required for chemokine-induced, sustained adhesion under flow in vivo., 2006; J Leukoc Biol. 80(6) 1491-9.
Zarbock A, Singbartl K, Ley K, Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation., 2006; J Clin Invest. 116(12) 3211-9.
Rychak JJ, Li B, Acton ST, Leppänen A, Cummings RD, Ley K, Klibanov AL, Selectin ligands promote ultrasound contrast agent adhesion under shear flow., 2006; Mol Pharm. 3(5) 516-24.
Whetzel AM, Bolick DT, Srinivasan S, Macdonald TL, Morris MA, Ley K, Hedrick CC, Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor., 2006; Circ Res. 99(7) 731-9.
Whetzel AM, Bolick DT, Srinivasan S, Macdonald TL, Morris MA, Ley K, Hedrick CC, Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor., 2006; Circ Res. 99(7) 731-9.
Rychak JJ, Lindner JR, Ley K, Klibanov AL, Deformable gas-filled microbubbles targeted to P-selectin., 2006; J Control Release. 114(3) 288-99.
Ley K, Zarbock A, Hold on to your endothelium: postarrest steps of the leukocyte adhesion cascade., 2006; Immunity. 25(2) 185-7.
Reutershan J, Morris MA, Burcin TL, Smith DF, Chang D, Saprito MS, Ley K, Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung., 2006; J Clin Invest. 116(3) 695-702.
Bachmann C, Klibanov AL, Olson TS, Sonnenschein JR, Rivera-Nieves J, Cominelli F, Ley KF, Lindner JR, Pizarro TT, Targeting mucosal addressin cellular adhesion molecule (MAdCAM)-1 to noninvasively image experimental Crohn's disease., 2006; Gastroenterology. 130(1) 8-6.
Smalley DM, Ley K, Plasma-derived microparticles for biomarker discovery., ; Clin Lab. 54(3) 67-79.
Ley K, Smith E, Stark MA, IL-17A-producing neutrophil-regulatory Tn lymphocytes., ; Immunol Res. 34(3) 229-42.