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Nigel Mackman, Ph.D.

Professor Adjunct
Department of Immunology and Microbiology
California Campus
Laboratory Website
Scripps VIVO Scientific Profile
nmackman@scripps.edu
(858) 784-8594

Research Focus

Crosstalk Between the Coagulation Protease Cascade and the Inflammatory Response

My laboratory studies the crosstalk between the coagulation protease cascade and inflammation. We have shown that bacterial LPS induces human monocytes to express the procoagulant protein tissue factor (TF) and inflammatory mediators, such as TNF . We use human monocytic cell lines and human monocytes to elucidate the positive and negative regulatory intracellular signaling networks and transcription factors that control expression of these procoagulant and inflammatory genes. In addition, we generate transgenic mice to examine the role of these proteins in in vivo models of disease. My laboratory is interested in elucidating how coagulation proteases contribute to inflammation in sepsis and in ischemia-reperfusion (I/R) injury. We hypothesize that in sepsis the coagulation proteases, factor Xa and thrombin, increase the expression of inflammatory mediators by activating protease activator receptors (PARs) that are expressed on endothelial cells. Recently, we showed that TF-dependent thrombin generation contributed to myocardial infarction by increasing the expression of inflammatory mediators in a rabbit model of cardiac I/R injury. We have extended these studies by establishing a mouse model of cardiac I/R injury. Using PAR-1-/- mice, we have found that PAR-1 contributes to infarct size probably via activation by thrombin. In future studies, we will generate transgenic mice that express PAR-1 on either endothelial cells or cardiomyocytes to determine the site of functional PAR-1 expression that contributes to cardiac I/R injury. Other studies will elucidate the mechanism by which PAR-1 contributes to cardiac I/R injury.

Education

Ph.D. (Genetics), University of Leicester 1985
B.Sc. (Molecular Biology), University of Leicester 1982

Professional Experience

2007-2017 Professor Adjunct, Immunology and Microbial Science (IMS), The Scripps Research Institute
2009-2011 Associate Director, UNC McAllister Heart Institute (MHI), The University of North Carolina at Chapel Hill
2002-2007 Associate Professor (with tenure), Department of Immunology, The Scripps Research Institute
1995-2002 Associate Professor, Department of Immunology, The Scripps Research Institute
1989-1995 Assistant Professor, Department of Immunology, The Scripps Research Institute
1987-1989 Postdoctoral Fellow, Scripps Clinic and Research Foundation
1985-1987 Postdoctoral Fellow, University of Leicester

Selected References

All Publications

Luther, T., Mackman, N. Tissue factor in the heart. Multiple roles in hemostasis, thrombosis and inflammation. Trends in Cardiovasc. Med. 11:307, 2001.

Melis, E., Moons, L., De Mol, M., Herbert, J.-M., Mackman, N., Carmeliet, P., Dewerchin, M. Normal development and survival of mice with deletion of the cytosolic domain of tissue factor. Biochem. Biophys. Res. Commun. 286:580, 2001.

Pendurthi, U.R., Meng, F., Mackman, N., Rao, V.M. Mechanism of resveratrol-mediated tissue factor gene expression. Thromb. Haemost. 87:155, 2002.

Bavendiek, U., Libby, P., Kilbride, M., Reynolds, R., Mackman, N., Schönbeck, U. Induction of tissue factor expression in human endothelial cells via CD40 ligand is mediated by Ap-1, NF- B, and Egr-1. J. Biol. Chem., in press.