BBS Faculty Member - Michael Gimbrone

Michael Gimbrone

Department of Pathology

Brigham and Women's Hospital
New Research Building, Rm 752
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-732-7514
Fax: 617-732-7513
Email: mgimbrone@rics.bwh.harvard.edu
Lab Members: 1 postdoctoral fellow, 1 research associate
Visit my lab page here.



The focus of our laboratory’s studies is the vascular endothelial cell, the single-cell-thick lining of the cardiovascular system. Using a combination of cell and molecular biological approaches, in both in vitro and in vivo model systems, we are attempting to define the role(s) of this dynamic and vital cell in health and disease.

In the mid-1980’s, our research group described the process of activation of vascular endothelium by humoral stimuli, such as proinflammatory cytokines (IL-1, TNF). This led to the discovery of “endothelial-leukocyte adhesion molecule” (ELAM-1, now designated E-selectin), the first example of an endothelial-specific, inducible leukocyte adhesion molecule important in inflammation. Molecular cloning of ELAM-1 revealed a new family of adhesion molecules – the Selectins – which are actively being explored as targets for anti-inflammatory therapies. Our laboratory also identified VCAM-1, as a mononuclear leukocyte-selective adhesion molecule that is induced, in arterial endothelial cells, by cytokines and components of oxidized lipoproteins, and marks the earliest lesions of atherosclerosis in vivo. Ongoing studies focus on the role of the activated endothelial cell in various disease processes.

In collaboration with bioengineering colleagues at MIT, our laboratory has developed in vitro fluid mechanical systems to examine the cellular and molecular responses induced in vascular endothelial cells by hemodynamic forces. Utilizing these in vitro model systems, we have previously characterized a “shear-stress-response element” (SSRE) in the promoter of the human PDGF-B gene, the first example of a cis-acting transcriptional regulator of endothelial gene expression by biomechanical forces. The subsequent characterization of additional SSREs, in other biomechanically regulated endothelial genes, has validated this mechanism of endothelial activation. Utilizing a differential display strategy, we also have described the induction of “atheroprotective genes” in endothelium by steady laminar shear stresses, which may be responsible for the resistance of certain vascular geometries to atherosclerotic lesion development.

We are currently applying high-thru-put transcriptional profiling and bioinformatic strategies to analyze the functional phenotypes of vascular endothelial cells in a variety of (patho)physiologic settings relevant to human disease pathogenesis. (see Website).



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Comander J, Natarajan S, Gimbrone MA Jr, Garcia-Cardena G. Improving the statistical detection of regulated genes from microarray data using intensity-based variance estimation. GMC Genomics 2004; 5:17.

Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn D, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone MA Jr. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and resistant regions of human vasculature. Proc. Natl. Acad. Sci. (USA) 2004: 101(41):14871-14876.

Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthi SN, Kratz JR, Lin Z, Jain M, Gimbrone MA Jr, Garcia-Cardena G. Integration of flow-dependent endothelial phenotypes by KLF2. J. Clin. Invest. 2006; 116(1):49-58.

Dai G, Vaughn S, Zhang Y, Wang ET, Garcia-Cardena G, Gimbrone MA Jr. Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via Phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ. Res. 2007; 101:723.



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