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
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.