My research focuses on characterizing intracellular signaling mechanisms which regulate endothelial cell functions and/or responses to environmental cues. Vascular injury has been implicated in the pathogenesis of disorders such as sepsis and acute respiratory distress syndrome (ARDS). Identification of molecules key in regulating endothelial cell functions may lead to therapeutic strategies for controlling vascular tissue damage and enhancing repair.

Biography

Saint Joseph's University, Philadelphia, PA, Biology, B.A.

Hahnemann University, Philadelphia, PA, Biological Chemistry, Ph.D.

Beth Israel Hospital, Cardiovascular Division, Harvard Medical School, Department of Medicine, Boston, MA, post-doctoral fellowship

Institutions

VAMC

Research Description

I currently recruiting a postdoctoral fellow to work on the projects listed below. Interested candidates should email their curriculum vitae and the names of three references to elizabeth_harrington@brown.edu.

Protein kinase C (PKC) is a family of twelve serine-threonine kinases. Each PKC isoform is thought to have its own discrete activators, cofactors, and substrates; however, few have been identified. PKC activity has been shown to be critical in endothelial cell functions, including proliferation, migration, adhesion, apoptosis, barrier function, tube formation, and cell cycle progression. Currently, we have two avenues of investigation underway.

The main goal of the first project is to elucidate the molecular mechanism(s) by which PKCdelta regulates endothelial monolayer permeability. We hypothesize that PKCdelta regulates endothelial basal barrier function by stabilizing adhesive forces of microfilaments and focal contacts through a RhoA GTPase-dependent signaling pathway.

The main focus of the second project is to elucidate signaling pathways which are differentially activated in microvascular endothelial cells in response to oxidative stress. Our hypothesis is that endothelial cells from pulmonary and systemic vascular beds differ in response to oxidative stress and subsequent induction of apoptosis.

Awards

Individual National Research Service Award, National Institutes of Health, 1 F32 HL09023-01A1, "Protein kinase C gene family and endothelium", 9/1994-9/1996

American Heart Association, Rhode Island Affiliate, Beginning Grant-in-Aid Award, 986005T, "Role of Protein Kinase C Isoenzymes in Endothelial Cell Adherens Junctions", 7/1998-10/1998

American Cancer Society, Institutional Grant IN-45-39, "Protein Tyrosine Phosphatase Modulation by Protein Kinase C and Endothelial Cell Function", 12/1997-11/1998

Department of Veterans Affairs, Merit Review Award, Type II, "Role of Protein kinase C isoenzymes in endothelial cell adherens junctions", 10/1998-9/2001

Affiliations

American Heart Association
American Society for Cell Biology
American Society for Biochemistry and Molecular Biology
American Thoracic Society

Funded Research

National Institutes of Health (NIH)/ National Heart, Lung, and Blood Institute (NHLBI) HL67795
"Endothelial Barrier Function Modulation by PKCdelta-"
Period of Support: 8/2001-1/2012
Principal Investigator

Department of Veterans Affairs, Merit Review
"Signaling in Hypoxic Pulmonary vs. Systemic Endothelium"
Period of Support: 7/2004-9/2007
Principal Investigator

Selected Publications

• Simon, A, Harrington, EO, Liu, G-X, Koren, G, Choudhary, G. Mechanisms of C-type Natriuretic Peptide-Induced Endothelial Cell Hyperpolarization. American Journal of Physiology, 296:L248-L256.(2009)
• Lu Q, Harrington EO, and Rounds S. TGF-(beta)1 Causes Pulmonary Microvascular Endothelial Cell Apoptosis via ALK5. American Journal of Physiology, 296:L825-L838.(2009)
• Fordjour, AK, Harrington, EO. PKCdelta influences p190 phosphorylation and activity: Events independent of PKCdelta-mediated regulation of endothelial cell stress fiber and focal adhesion formation and barrier function. Biochimica et Biophysica Acta 1790: 1179-1190.(2009)
• Martin, K, Stanchina, M, Kouttab, N, Harrington, EO, Rounds, S. Circulating Endothelial Cells and Endothelial Progenitor Cells in Obstructive Sleep Apnea. Lung 186:145-150.(2008)
• Lu, Q, Harrington, EO, Newton, J, Jankowich, M, Rounds, S. Inhibiton of ICMT induces endothelial cell apoptosis through GRP94. American Journal of Respiratory Cell and Molecular Biology 37:20-30.(2007)
• Sanchez, T, Skoura, A, Wu, MT, Casserly, B, Harrington, EO, Hla, T. Induction of Vascular Permeability by the Sphingosine-1-phosphate receptor-2 (S1P2R) and its Downstream Effectors ROCK and PTEN. Arteriosclerosis, Thrombosis and Vascular Biology 37:1312-1318.(2007)
• Klinger JR, Murray JD, Casserly B, Alvarez DF, King JA, An SS, Choudhary G, Owusu-Sarfo AN, Warburton R, Harrington EO. Rottlerin causes Pulmonary Edema in vivo: A Possible Role for PKC{delta}. Journal of Applied Physiology 103:2084-2094.(2007)
• Klinger, JR, Warburton, RR, Carino, GP, Murray, J, Murphy, C, Napier, M, Harrington, EO. Natriuretic peptides differentially attenuate thrombin-induced barrier dysfunction in pulmonary microvascular endothelial cells. Experimental Cell Research 312:401-10.(2006)
• Harrington, EO, Stefenac, T, Newton, J, Rounds, S. Apoptosis causes soluble E-selectin release from activated endothelial cells. Lung 184:259-266.(2006)
• Lu, Q, Harrington, EO, Jackson, H, Morin, N, Shannon, CJ, Rounds, S. Transforming growth factor-beta1-induced endothelial barrier dysfunction involves SMAD2-dependent p38 activation and subsequent RhoA activation Journal of Applied Physiology 101:375-384.(2006)
• Harrington, EO, Shannon, CJ, Morin, N, Rowlett, H, Murphy, C, Lu, Q. PKCdelta regulates endothelial basal barrier function through modulation of RhoA GTPase Activity. Experimental Cell Research 308:407-421.(2005)
• Lu, Q, Harrington, EO, Rounds, S. Apoptosis and lung injury. Keio Journal of Medicine 54:184-189.(2005)
• Harrington, EO , Newton, J, Morin, N, Rounds, S. Barrier Dysfunction and RhoA Activation are Blunted by Homocysteine and Adenosine in Pulmonary Endothelium. American Journal of Physiology 287:L1091-L1097.(2004)
• Tsikitis, VL, Morin, NA, Harrington, EO , Albina, JE, Reichner, JS. The lectin-like domain of complement receptor 3 protects endothelial barrier function from activated neutrophils. Journal of Immunology 173:1284-1291.(2004)
• Lu Q, Harrington EO , Hai CM, Newton J, Garber M, Hirase T, Rounds S. Isoprenylcysteine carboxyl methyltransferase modulates endothelial monolayer permeability: Involvement of RhoA carboxyl methylation. Circulation Research, 94:306-315 .(2004)
• Harrington, EO , Brunelle, JL, Shannon, CJ, Kim, ES, Mennella, K, Rounds, S. Role of protein kinase C isoforms in rat epididymal microvascular endothelial barrier function. American Journal of Respiratory Cell and Molecular Biology, 28:626-636.(2003)
• Kramer, K, Harrington, EO , Bellas, R, Sheahan, KL, Newton, JL, Rounds, S. Isoprenylcysteine carboxyl methyltransferase activity modulates endothelial cell apoptosis. Molecular Biology of the Cell, 14:848-857.(2003)
• Bellas, RE, Harrington, EO, Sheahan, KL, Newton, J, Marcus, C, Rounds, S. FAK blunts adenosine/homocysteine-induced endothelial cell apoptosis: Requirement for PI 3-kinase. American Journal of Physiology: Lung Cellular and Molecular Physiology. 282:L1135-L1142.(2002)
• Harrington, EO, Smeglin, A, Newton, JL, Ballard, G, Rounds, S. Protein tyrosine phosphatase-dependent proteolysis of focal adhesion complexes in endothelial cell apoptosis. American Journal of Physiology: Lung Cellular and Molecular Physiology: 280:L342-L353.(2001)