Dr. Aly Karsan, MD
Head of Clinical Diagnostic Genomics, Michael Smith Genome Sciences Centre, BC Cancer Agency
Professor, Department of Pathology and Laboratory Medicine, University of British Columbia
- Myelodysplastic syndromes
- Innate immune signaling in vascular and hematopoietic function
- Role of Notch in cardiovascular development and angiogenesis
My lab focuses on two major areas:
(1) Understanding the molecular basis of the preleukemic bone marrow failure conditions called myelodysplastic syndromes (MDS); and
(2) Determining the role of the endothelium in the development of the hematopoietic system. With respect to both areas we have been studying the role of two pathways: innate immune signaling as represented by the Toll-like receptor (TLR) pathways, and the Notch signaling pathway.
We have recently demonstrated that microRNAs that reside on the long arm of chromosome 5 act to regulate innate immune signaling. Deletion of chromosome arm 5q is the commonest structural anomaly seen in MDS, and our current work is centred around establishing the function of these microRNAs and deregulated innate immune signaling in the manifestations of MDS. We are using a variety of in vivo transplantation assays, in vitro cell biology and cell signaling studies as well as genomic approaches to answer these questions.
In other work related to innate immune signaling, we have identified a novel protein by differential proteomic analysis that appears to act as a scaffold protein in a MyD88-independent TLR signal transduction pathway. Expression analyses indicate that this molecule is highly expressed in the microvasculature. Molecular and cellular studies to elucidate the mechanisms of action of this protein are ongoing. As well we have generated a gene-targeted mouse model that demonstrates that loss of this protein is incompatible with life past mid-gestation. Currently, we are generating a conditional gene-targeted mouse model to gain a better understanding of the physiologic role of this protein.
My lab has also had a long-standing interest in the role of Notch signaling in the endothelium. We have generated a conditional, inducible mouse model in which we are able to regulate Notch signaling. Using this and other models we are studying how endothelial cells contribute to hematopoietic development both at the initial stages of intraembryonic hematopoiesis where hematopoietic stem cells are thought to derive from the endothelium, as well as during fetal liver and adult hematopoiesis, where the endothelium may act as a niche to regulate stem cell self renewal and/or differentiation.
Chang L, Noseda M, Higginson M, Ly M, Patenaude A, Fuller M, Kyle AH, Minchinton AI, Puri MC, Dumont DJ, Karsan A. Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6993-8. Epub 2012 Apr 16. PMID: 22509029; PubMed Central PMCID: PMC3345008. Author's final copy
Starczynowski DT, Lockwood WW, Deléhouzée S, Chari R, Wegrzyn J, Fuller M, Tsao MS, Lam S, Gazdar AF, Lam WL, Karsan A. TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer. J Clin Invest. 2011 Oct 3;121(10):4095-105. doi: 10.1172/JCI58818. Epub 2011 Sep 12. PubMed PMID:21911935; PubMed Central PMCID: PMC3195480.
Chang AC, Fu Y, Garside VC, Niessen K, Chang L, Fuller M, Setiadi A, Smrz J, Kyle A, Minchinton A, Marra M, Hoodless PA, Karsan A. Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell. 2011 Aug 16;21(2):288-300. PubMed PMID: 21839921.
Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, Hirst M, Hogge D, Marra M, Wells RA, Buckstein R, Lam W, Humphries RK, Karsan A. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010 Jan;16(1):49-58. Epub 2009 Nov 8. PubMed PMID: 19898489. Authors Proof
Titles and Education
Head, Clinical Diagnostic Genomics, BC Cancer Agency
Medical Director, Cancer Genetics Laboratory, Pathology and Laboratory Medicine, BC Cancer Agency
Professor, Pathology and Laboratory Medicine, University of British Columbia
Member, Experimental Medicine, University of British Columbia
Founding Member, Centre for Blood Research, University of British Columbia
Member, Stem Cell Network
B.A. (Life Sciences), Queens University, 1983
M.D., Queens University, 1986