Christopher V. Carman, Ph.D.
Assistant Professor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-234
Boston, MA 02215
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.
Research Interests: Vascular & Cell Biology of Inflammation and Wound Healing
Basic Research - My laboratory investigates the cell biological basis of inflammation and wound healing with special emphasis on leukocyte-endothelial interactions. The vascular endothelium is the monolayer of cells that lines the cardiovascular system and provide as the critical barrier between the tissues and the blood. Thus, the endothelium is strategically positioned to serve as a unique sentinel for communicating interstitial information to the circulating immune cells (i.e., leukocytes). In this way, the endothelium plays critical roles in directing the trafficking patterns, as well as activation states, of leukocytes. The endothelium can also become damaged by inappropriate immune/inflammatory responses, creating a dysfunctional barrier that gives rise to many of the pathogenic features of inflammatory diseases such as sepsis, ischemia-reperfusion injury, anaphylaxis, atherosclerosis and arthritis. Our work makes extensive use of advanced fluorescence imaging and electron microscopy alongside, biochemical, pharmacologic and biomechanical approaches to understand fundamental mechanisms of protective versus pathologic inflammation. Topics we are currently investigating include:
Leukocyte and Stem Cell Trafficking. A crucial regulatory step in the trafficking (and therefore function) of immune and stem cells is the crossing of the endothelial barrier (i.e., 'transendothelial migration' or 'diapedesis'). We are interested in the fundamental adhesive, migratory, invasive (i.e., barrier breaching) and signaling mechanisms that govern this process. We are particularly, interested in how normally protective/homeostatic leukocyte-endothelial interactions become perturbed by environmental changes associated with inflammatory disease. For example, we are addressing effects of ischemia-reperfusion (e.g., heart attach, stroke), systemic infection (e.g., sepsis) and stiffening of substrates/vessels (e.g., atherosclerosis) on leukocyte adhesion, migration and activation.
Endothelial Integrity and Wound Healing. We are interested in better understanding the rudimentary basis for vascular endothelial integrity and regulation barrier function. Physically, the endothelium is a remarkable tenuous cell monolayer, often only a few hundred nanometers thick. Yet, in vivo the endothelium normally exhibits an extremely effective and durable barrier function and withstands constant mechanical strains including fluid shear flow, variable stretch, hydrostatic pressure and trafficking of leukocytes. Our ongoing studies suggest that the success of the endothelium as a barrier depends on an enormous self-restorative capacity that is driven by perpetual actin remodeling. Our findings also forward the counter intuitive idea that endothelial integrity relies on NADPH oxidase-mediated reactive oxygen species generation, a concept that may have important implications for understanding precisely how oxidative stress contributes to cardiovascular disease. Finally, we are actively screening for agents that promote vascular endothelial integrity, which could serve as new therapeutics for a broad range of vascular leak pathologies (e.g., sepsis, burn and traumatic shock, ischemia-reperfusion injury, ALI, TRALI, ARDS, VILI).
Adaptive Immune Functions of the Endothelium .Endothelial cells express MHC (major histocompatibility complex) and co-stimulatory molecules and are thought to represent a population of peripheral 'semi-profession' antigen presenting cells (APCs). 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. Our studies implement novel in vitro imaging approaches to characterize the T cell-endothelial cell 'immunological synapses'. Additionally, we have designed unique genetic approaches to elucidate the overall functional roles for the endothelium in adaptive immune responses in vivo and in mediating effects of emerging APC-dependent immuno-modulatory therapies.
'Bedside-to-Bench' Investigation of Human Disease. In order to better understand the cellular and molecular underpinnings of human inflammatory disease, we have developed a 'bedside-to-bench' approach, whereby patient blood and biopsies are subject to ex vivo characterization (e.g., flow cytometric, biochemical and transcriptomic analysis) and cell biological experimentation. We are implementing this approach toward understanding of the pathogenic mechanisms of acute both infectious (e.g., sepsis) and sterile (e.g., trauma), well as chronic (e.g., arthritis) inflammatory pathology. We hope that the insights gained from this type of clinically relevant, basic research will facilitate more effective translation to new diagnostics, prognostics and therapeutics.
New and Noteworthy Publications:
Martinelli R, Zeiger AS, Whitfield M, Sciuto TE, Dvorak AM, Van Vliet KJ, Greenwood J, Carman CV. Probing the biomechanical contribution of the endothelium to lymphocyte migration: Diapedesis by the path of least resistance. J Cell Sci, 2014; 127:3720-34. (Highlighted - In This Issue: J Cell Sci, 2014; 127: e1704). This study defines a new migratory process, termed ‘tener-taxis’ (Latin tener, soft, tenuous), whereby leukocytes use invadosome-like protrusions to dynamically sample the mechanical properties (i.e., stiffness) of their environment in order to facilitate barrier breaching at permissively ‘soft’ or ‘tenuous’ locations.
Zonneveld R, Martinelli R, Shapiro NI, Kuijpers TW, Plotz FB, Carman CV. Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults. Crit Care. 2014; 18:204 (Highlighted – Commentary, Crit Care, 2014; 18;121). This paper reviews the current state-of-the-art in sepsis biomarker research and forwards a new hypothesis that concomitant monitoring of both soluble adhesion markers and circulating ‘sheddases’ may provide an improved diagnostic and prognostic approach.
Martinelli R, Kamei M, Sage PT, Massol R, Varghese L, Sciuto T, Toporsian M, Dvorak AM, Kirchhausen T, Springer TA, Carman CV. Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds. J Cell Biol, 2013; 201:449-65. (Highlighted - JCB BioSights Podcast, May, 2013). This study demonstrates that the vascular endothelium uses mechanical tension to sense the quality of its barrier and implements newly uncover actin remodeling dynamics (i.e., ‘ventral lamellipodia’) to recover and maintain its integrity. It also forwards the counterintuitive idea that endothelial integrity depends of reactive-oxygen species.
Teo GS, Ankrum JA, Martinelli R, Boetto SE, Simms K, Sciuto TE, Dvorak AM, Karp JM, Carman CV. Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-α-activated endothelial cells via both leukocyte-like and novel mechanisms. Stem Cells, 2012; 30:2472-86. This study characterized for the first time the cellular and molecular basis for MSC transendothelial migration and uncovers a unique alternative to leukocyte actin protrusions, namely non-apoptotic membrane blebbing, for breaching the endothelium and initiating diapedesis.
Carman CV, Sage PT, Sciuto TE, de la Fuete MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. Trans-cellular diapedesis is initiated by invasive podosomes. Immunity, 2007; 26:784-97 (Highlighted – Previews: Immunity, 2007; 26:753-5). This study describes a new protrusive organelle in leukocytes, termed ‘invasive-podosomes’ (a.k.a., ‘invadopodia-like protrusions’), that facilitates their trafficking by promoting the breaching of the endothelial barrier.
Carman CV, Springer TA. A Transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol, 2004; 167:377-88 (Highlighted - In This Issue: J Cell Biol, 2004; 167:189). This study was the first to provide conclusive demonstration of the trans-cellular mode of leukocyte diapedesis and also describes a novel actin-dependent endothelial structure (i.e., a ‘transmigratory cup’) that guides leukocyte directionality during extravasation.