Mark Collinge, Ph.D. Associate Research Scientist

B.S., University of Nottingham, England, 1985; Ph.D., University of Edinburgh, Scotland, 1988; Postdoctoral Fellow (Pharmacology) Vanderbilt University Medical School, 1989-1992; Research Instructor, Vanderbilt University Medical School, 1993-1994; Research Assistant Professor, Northwestern University Medical School, 1994-1996; joined Yale Faculty 1996.

Research Interests

Vascular endothelial cells (EC) can be primary targets for circulating immune effector cells, leading to vascular pathogenesis and ultimate organ dysfunction. Endothelial cell activation is believed to be a major component in both allo- and xenograft rejection, and can be achieved either by cytokine (for example IFN-g) stimulation, or interaction with immune cells, for example Natural Killer (NK) cells. The process of activation is a complex program of events coordinated by alterations in gene expression and subsequent cellular function.

One specific area of research interest lies in defining the molecular mechanisms leading to endothelial cell activation by NK cells. NK cells are the most efficient cellular inducers of Major Histocompatibiltity Complex (MHC) class II molecules on the surface of allogeneic endothelial cells, and also induce a variety of endothelial cell adhesion molecules. The induction of MHC class II gene expression is adhesion-dependent and requires interaction between cell surface counter-receptors, the b2 integrins and Intercellular Adhesion Molecules (ICAM). Although NK cells are competent producers of IFN-g , we have demonstrated, using a series of mutant cell lines defective for IFN-g signaling, that the induction of MHC II by NK cells can be achieved through IFN-g- independent mechanisms. NK:EC adhesion leads to direct transmembrane signaling and the aim of this specific line of research is to identify and characterize the molecular mechanisms responsible for contact-dependent MHC class II gene induction. The overall aim is to understand the adhesion-dependent events which lead to endothelial cell activation by NK cells in general. Using the approach of subtractive hybridization we have isolated a number of endothelial cell gene products induced by NK cell adhesion, and are in the process of characterizing these in terms of their molecular structure and function. For example, one such gene product, encoded within the MHC class I locus, bears sequence similarity to the ubiquitin family of molecules . Ubiquitins are involved in protein degradation, protein trafficking and chaperone functions. Based on the structure of this novel molecule and its gene location we are currently investigating its mode of expression, subcellular location, and possible involvement in antigen presentation and cell cycle regulation.

The b2 integrin LFA-1 (lymphocyte function associated antigen-1) contributes to the strong adhesion observed between T-lymphocytes and antigen presenting cells. LFA-1 mediates transmembrane signaling leading to T-cell activation (increased cytokine production and cellular proliferation). We have observed that in a costimulatory fashion LFA-1 is able to induce expression of specific protein moieties, including urokinase plasminogen activator receptor (uPAR), and that this is primarily attributable to messenger RNA stabilization. One specific region involved in mRNA stabilization has been identified within the 3' nontranslated region of uPAR mRNA, and is a motif common to a number of cytokines and cellular proto-oncogenes. The molecular events underlying mRNA stabilization induced by LFA-1 co-stimulation are under investigation.


Liu Y-C, Pan J, Zhang C, Fang W, Collinge M, Bender JR, Weissman SM: An MHC encoded ubiquitin-like protein (FAT10) binds noncovalently to a spindle assembly checkpoint protein MAD2. Proc. Natl Acad. Sci. USA 96:4313-4318, 1999.

Collinge M, Pardi R, Bender JR: Class II transactivator-independent endothelial cell MHC class II gene activation induced by lymphocyte adhesion. The Journal of Immunology, 161:1589-1593, 1998.

Wang GJ, Collinge M, Blasi F, Pardi R, Bender, JR: Postranscriptional regulation of urokinase plasminogen activator receptor messenger RNA levels by leukocyte integrin engagement. Proc. Natl Acad. Sci. USA, 95:6296-6301, 1998.

Sadeghi, M.M., Collinge, M., Pardi, R., Bender, J.R.: Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: Involvement of an inhibitory G-protein. The Journal of Immunology, 165: 2712-2718, 2000.

Haynes, M.P., Sinha, D., Russell, K.S., Collinge, M., Fulton, D., Morales-Ruiz, M., Sessa, W.C., Bender, J.R.: Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the P13-kinase-Akt pathway in human endothelial cells. Circ. Res. 87:677-682, 2000.

Sadeghi, M.M., Tiglio, A., Sadigh, K., O’Donnell, L., Collinge, M., Pardi, R., and Bender, J.R.: Inhibition of Interferon-g-Mediated Microvascular Endothelial Cell Major Histocompatability Complex Class II Gene Activation by HMG-CoA Reductase Inhibitors. Transplantation. 70:1262-1268, 2001.

Rossetti, G., Collinge, M., Bender, J.R., Molteni, R., Pardi,R.: Integrin-dependent regulation of gene expression in leukocytes. Immunol. Rev., 186:189-207,2002.

Haynes, P., Li, L., Sinha, D., Russell, K.S., Collinge, M., Hisamoto,K., Baron, R., Sessa, W., Bender, J.R.: Src kinase mediates phosphatidylinositol 3-kinase/Akt dependent rapid endothelial nitric oxide synthase activation by estrogen. J.Biol. Chem., 278:2118-2123, 2003.

Wang, J., Collinge, M., Ayalon, A., Xinhao, C.F., Pardi, R., Bender, J.R: LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. Submitted for publication.

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Last modified: Friday, 12-Dec-2003 08:56:36 EST (PL).