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Michael A. Gimbrone, MD
Senior Pathologist, Brigham and Women's Hospital
Elsie T. Friedman Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115


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Research Narrative:

The focus of the Gimbrone laboratory is the vascular endothelial cell, the single-cell-thick lining of the cardiovascular system. A combination of cell and molecular biological approaches, in both in vitro and in vivo model systems, are being employed to investigate the role(s) of this dynamic and vital cell in health and disease.

In the mid-1980’s, the 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. The 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, the Gimbrone laboratory has developed in vitro fluid mechanical systems to examine the cellular and molecular responses induced in vascular endothelial cells by hemodynamic forces. These in vitro model systems enabled the characterization of 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, the Gimbrone laboratory has 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.

Current projects include: the application of 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; and exploration of the effects of progerin (the mutant gene product in Hutchinson-Gilford Progeria Syndrome) on endothelial pathobiology, utilizing a model system in which cultured human endothelial cells express progerin via adenoviral infection
 


Education:
MD

Lab Members:
Belinda Yap, PhD, Postdoctoral Fellow

Publications (Pulled from Harvard Catalyst Profiles):

1. Gimbrone MA, García-Cardeña G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016 Feb 19; 118(4):620-36.

2. Gimbrone MA, García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol. 2013 Jan-Feb; 22(1):9-15.

3. Gimbrone MA. The Gordon Wilson lecture. Understanding vascular endothelium: a pilgrim's progress. Endothelial dysfunction, biomechanical forces and the pathobiology of atherosclerosis. Trans Am Clin Climatol Assoc. 2010; 121:115-27; discussion 127.

4. Nathan DG, Gimbrone MA. Judah Folkman, MD, 1933-2008. Pharos Alpha Omega Alpha Honor Med Soc. 2009; 4-8.

5. Dai G, Vaughn S, Zhang Y, Wang ET, Garcia-Cardena G, Gimbrone MA. Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ Res. 2007 Sep 28; 101(7):723-33.

6. García-Cardeña G, Gimbrone MA. Biomechanical modulation of endothelial phenotype: implications for health and disease. Handb Exp Pharmacol. 2006; (176 Pt 2):79-95.

7. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA, García-Cardeña G. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest. 2006 Jan; 116(1):49-58.

8. Parmar KM, Nambudiri V, Dai G, Larman HB, Gimbrone MA, García-Cardeña G. Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. J Biol Chem. 2005 Jul 22; 280(29):26714-9.

9. Lin Z, Kumar A, SenBanerjee S, Staniszewski K, Parmar K, Vaughan DE, Gimbrone MA, Balasubramanian V, García-Cardeña G, Jain MK. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res. 2005 Mar 18; 96(5):e48-57.

10. Gimbrone MA Jr. . Hemodynamic forces as modulators of endothelial gene expression in health and disease. Foundation IPSEN Colloquium, Life and Death of the Vascular Tree, Paris. 2005.