Christopher Carman, PhD
Assistant Professor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-234
Boston, MA 02215
Carman Lab >>
Chris Carman earned a Ph.D. in Molecular Pharmacology and Structural Biology from Thomas Jefferson University, Philadelphia, PA in 1999. He then performed a post-doctoral study at Harvard Medical School with Timothy A. Springer. In 2006 Dr. Carman joined the Division of Molecular and Vascular Medicine at Beth Israel Deaconess Medical Center and became a member of the CVBR.
My laboratory investigates the cell biological basis of inflammation with special with emphasis on leukocyte-endothelial interactions, critical determinants of inflammatory responses. Our work makes extensive use of advanced fluorescence imaging and electron microscopy to understand the fundamental basis and consequences of these interactions and how they may become perturbed during inflammatory and immune-related disease. Topics we are currently investigating include i.) the basis and regulation of leukocyte trafficking (i.e. trans-endothelial migration), ii.) the role of the endothelium as an antigen presenting cell, and iii.) the development of novel approaches for endothelial-targeted delivery of small molecules and siRNA.
We are investigating the signaling and cytoskeletal regulation involved in leukocyte migration across the endothelial barrier. We have recently uncovered, and are further characterizing, roles for actin dependent protrusive organelles, termed 'podosomes' in the process of leukocyte migratory pathfinding. We are also studying the roles for endothelial cytoskeleton in modulating the transmigration process and restoring barrier function after transmigration events.
Endothelial Antigen Presentation
Endothelial cells express MHC (major histocompatibility complex) and co-stimulatory molecules and can promote antigen-specific stimulation of T lymphocytes. Specific roles for endothelial antigen presentation remain unclear, but have become increasing associated with auto-immune and inflammatory diseases including, allograft rejection, multiple sclerosis, diabetes, lupus and arthritis. One of our current goals is to elucidate the fundamental cellular basis for antigen recognition and responses at this locus (i.e. the lymphocyte-endothelial immunological synapse).
We have recently developed antibody-coupled liposome-based nano-particles for targeted siRNA delivery (Peer, et.al., Science, 2008). This strategy was effectively used to abrogate inflammatory bowel disease in vivo (using murine models) by targeting subsets of inflammatory lymphocytes. We are currently extending this approach to target the vascular endothelium as both an experimental approach and potential therapeutic.
New and Noteworthy Publications
View all publications via PubMed >>
Peer D, Park EJ, Morishita Y,
Carman CV, Shimaoka M. (2008) Systemic leukocyte-directed siRNA delivery revealing cycln D1 as an anti-inflammatory target. Science 319, In Press.
This study describes a novel and highly effective system for targeted delivery of siRNA to selected tissues in vivo that may have broad application as both an experimental tool and therapeutic strategy.
Carman CV, Sage PT, Sciuto TE, de la Fuete MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. (2007) Trans-cellular diapedesis is initiated by leukocyte podosomes. Immunity 26, p784.
This study describes a novel and highly dynamic property of leukocytes to physically 'probe' or 'palpate' the surface of the endothelium via protrusive organelles termed podosomes. One demonstrated function for this probing activity was to facilitate migratory pathfinding.
Carman CV, Springer TA. (2004) A Transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J .Cell Biol. 167, p377.
This study was the first to provide conclusive demonstration the trans-cellular mechanism for leukocyte trans-endothelial migration and also described a novel mechanism by which endothelium guides diapedesis.
*Kim, M., *
Carman, C.V. and Springer, T.A. (2003) "Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins." Science 301, p1720. *Contributed Equally.
This study, using a FRET imaging approach, was the first to demonstrate a specific conformation mechanism for the modulation of integrin adhesiveness in intact cells.
Carman, C.V., Jun, C.-D., Salas, A. and Springer, T.A. (2003) "Endothelial cells proactively form microvilli-like membrane projections upon intercellular adhesion molecule 1 engagement of leukocyte LFA-1." J. Immunol. 171, p6135.
This study was one of the first to demonstrate, that in response to leukocyte adhesion, endothelial cells proactively rearrange their actin cytoskeletons to facilitated enhanced cell-cell contact.