Philip Marsden
MD
I have a research program in the field of cellular and molecular regulation of endothelial gene expression.
The lab is focused on understanding the contribution of endothelial cells to human health and disease.
We are especially motivated towards understanding the contribution of important endothelial genes to disease processes and novel aspects of how endothelial genes are regulated.
Research Synopsis
Release of NO from the vascular endothelium represents a sensitive and highly effective local system for maintaining local blood flow to an organ.
This research laboratory played a major role in the cloning and functional characterization of endothelial NO synthase (eNOS) cDNAs and in the demonstration that expression of this endothelial gene is perturbed in atherosclerosis.
Recent studies seek to define the structure and organization of the eNOS gene and examine mechanisms of regulation that are relevant to the pathobiology of endothelial cells.
Current work focuses upon newer aspects of the transcriptional and post-transcriptional regulation of eNOS mRNA in development and disease.
Exciting new information indicates that chromatin structure, histone modifications and DNA methylation play a novel role in the cell-restricted expression of this important endothelial gene. Furthermore, RNA binding proteins and anti-sense RNA interactions play an unexpected role in regulation of endothelial NO synthase expression.
We have now begun studies to define the contribution of Dicer and RNA interference pathways to the regulation of eNOS and other endothelial cell genes.
The study of endothelial cells has also provided unique insight into important cardiovascular diseases and the control of angiogenesis during tumour development.
The control of new blood vessel formation, or angiogenesis, is orchestrated by vascular endothelium and endothelial cells respond to unique signals in their environment with a repertoire of cellular and molecular responses.
Other studies directed towards dissecting the molecular mechanisms underlying alterations in genotype and phenotype are underway in our lab using prototypic endothelial cell gene products (e.g. endothelin-1, eNOS, CXCR4, adhesion molecules such as VCAM-1 or ICAM-1) and exciting models of cellular activation (hypoxia, shear stress and epigenetic modifiers).
An excellent example of the applicability of this approach is our recent finding that shigatoxins, bacterial-derived exotoxins that cause severe inflammation of capillary beds in patients with E coli 0157:H7, regulate the expression of genes in vascular endothelium at the post-transcriptional level.
Recent Publications
Ho, J.J.D., Marsden, P.A. Posttranscriptional adaptations of the vascular endothelium to hypoxia, Current Opinion Hematology. 2015 May;22(3):243-51. doi: 10.1097/MOH.0000000000000139. PMID: 25767954
Turgeon, P.J., Sukumar, A.N., Marsden, P.A. Epigenetics of Cardiovascular Disease - A New "Beat" in Coronary Artery Disease. Med Epigenet. 2014
Cybulsky, M.I. and Marsden, P.A. Effect of disturbed blood flow on endothelial cell gene expression: a role for changes in RNA processing. Arterioscler Thromb Vasc Biol. 34:1806-8, 2014.
Ho, J.J.D., Marsden, P.A. Competition and collaboration between RNA-binding proteins and microRNAs. Wiley Interdiscip Rev RNA, 5: 69-86, 2014.
Das, S. Marsden, P.A. Angiogenesis in glioblastoma, NEJM, 369: 1561-1563, 2013.
Petruzziello-Pellegrini, T.N., Moslemi-Naeini, M., Marsden, P.A. New insights into shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome. Virulence, 4:556-563, 2013. Ho, J.J.D., Robb, G.B., Tai, S.C., Turgeon, P.J., Mawji, I.A., Man, H.S.J., Marsden. P.A. Active stabilization of the human endothelial nitric oxide synthase mRNA by hnRNP E1 protects against antisense RNA and microRNAs. Molecular and Cellular Biology 33:2029-2046, 2013.
Shirodkar, A.V., St. Bernard, R., Gavryushova, A., Kop, A. Knight, B.J., Yan, M.S., Man, H.S.J., Sud, M., Hebbel, R.P., Oettgen, P., Aird, W.C., Marsden, P.A. A mechanistic role for DNA methylation in endothelial cell (EC)-enriched gene expression: relationship with DNA replication timing. Blood. 121: 3531-3540, 2013
Ho, J.J., Metcalf, J.L., Yan, M.S., Turgeon, P.J., Wang, J.J., Chalsev, M., Petruzziello-Pellegrini, T.N., He, J.Z., Dhamko, H., Man, H.S., Robb, G.B., Teh, B.T., Ohh, M., Marsden, P.A. Functional importance of dicer protein in the adaptive cellular response to hypoxia. J Biol Chem 287:29003-20, Epub June 28, 2012.