Asrar B Malik

We are pursuing studies in three related areas: A major interest of the laboratory is to understand the regulation of the barrier properties of endothelial and epithelial cells. Dr. Malik's laboratory studies the events that occur at the level of receptors and the signaling pathways that regulate the barrier function of these monolayers. As thrombin has been shown to increase endothelial permeability, we are studying, using this agonist, how the activation of its proteolytically cleaved receptor leads to the observed increase in permeability. Studies have localized the domains of the receptor involved in both activation and inactivation of endothelial cell signaling. Researchers are exploring ways to inhibit the thrombin-induced barrier dysfunction by such as by introducing dominant negative forms of the receptor to inhibit thrombin receptor activation. Studies are also characterizing cellular effector pathways that increase vascular permeability to understand how the activation of the signaling pathways mobilizes these effectors (i.e., actin-myosin motor, cadherin-catenin complex and the intermediate cytoskeletal filaments).

An additional objective of the laboratory is to develop and test novel strategies for drug delivery. We are specifically interested in targeting cells of the vessel wall which are critical in the pathogenesis of inflammatory diseases, atherosclerosis, and cancer metastasis. The intent is to prevent, in a specific manner, the expression of endothelial adhesion molecules. Among the approaches being studied include the selective expression, using inducible promoters target the expression of "anti-adhesive" proteins in endothelial cells. We are also developing non-viral means including nanoparticles of delivery to transduce endothelial proteins of interest. The approaches taken involve molecular biology as well as physiological monitoring in genetic mouse models.

Finally, we are studying mechanisms of regeneration of injured vessels, specifically through lineage tracing studies of endothelial cells. These studies also entail defining transcriptional and signaling mechanisms of differentiation of ESCs to endothelial cells and developing strategies of using these cells to repair vascular injury and restore organ function.

Distinguished Research Achievement Award, American Thoracic Society
Dickinson Richards Lecture, American Heart Association

Visiting Professor at John Curtin School of Medical Research, Canberra, Australia

Scientific Advisory Council, Max Planck Institute of Cardiovascular Biology, Bad Nauheim

Board of Scientific Counselors, NIDCR, National Institutes of Health, Bethesda, MD

Research Acievement Award of Shock Society

Keynote Lecture, University of Zurich, Center for Integrative Human Physiology

Centennial Scholar Award, Institute of Medicine, Chicago

Fellow of the American Physiological Society

Fellow of the American Association of Advancement of Science

Research to Prevent Blindness Stein Innovation Award

Gong H, Gao X, Feng S, Siddiqui MR, Garcia A, Bonini MG, Komarova Y, Vogel SM, Mehta D, Malik AB. Evidence of a common mechanism of disassembly of adherens junctions through Gα13 targeting of VE-cadherin. J Exp Med. In Press.

Tiruppathi C, Soni D, Wang DM, Xue J, Singh V, Thippegowda PB, Cheppudira BP, Mishra RK, Debroy A, Qian Z, Bachmaier K, Zhao YY, Christman JW, Vogel SM, Ma A, Malik AB. The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. Nat Immunol. 15:239-47, 2014.

Hecquet CM, Zhang M, Mittal M, Vogel SM, Di A, Gao X, Bonini MG, Malik AB. Cooperative Interaction of trp Melastatin Channel Transient Receptor Potential (TRPM2) With Its Splice Variant TRPM2 Short Variant Is Essential for Endothelial Cell Apoptosis. Circ Res. 114:469-79, 2014.

Wang Z, Li J, Cho J, Malik AB. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nat Nanotechnol. 9:204-10, 2014.

Komarova YA, Huang F, Geyer M, Daneshjou N, Garcia A, Idalino L, Kreutz B, Mehta D, Malik AB. VE-cadherin signaling induces EB3 phosphorylation to suppress microtubule growth and assemble adherens junctions. Mol Cell. 48:914-25, 2012.

Vandenbroucke St Amant E, Tauseef M, Vogel SM, Gao XP, Mehta D, Komarova YA, Malik AB. PKCα activation of p120-catenin serine 879 phospho-switch disassembles VE-cadherin junctions and disrupts vascular integrity. Circ Res. 2012 Aug 31;111(6):739-49.

Di A, Gao XP, Qian F, Kawamura T, Han J, Hecquet C, Ye RD, Vogel SM, Malik AB. The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. Nat Immunol. 3:29-34, 2011.

Mirza MK, Sun Y, Zhao YD, Potula HH, Frey RS, Vogel SM, Malik AB, Zhao YY. FoxM1 regulates re-annealing of endothelial adherens junctions through transcriptional control of beta-catenin expression. J Exp Med. 207:1675-85, 2010.

Zhao YY, Zhao YD, Mirza MK, Huang JH, Potula HH, Vogel SM, Brovkovych V, Yuan JX, Wharton J, Malik AB. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest. 119:2009-18, 2009.

Bachmaier, K, Toya S, Gao X, Triantafillou T, Garrean S, Park GY, Frey RS, Vogel S, Minshall R, Christman JW, Tiruppathi C, Malik AB. E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nat Med. 8:920-6, 2007.