Research Interests
- 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.
For More Information about the Karsan Lab
Recent Publications
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
Starczynowski DT, Morin R, McPherson A, Lam J, Chari R, Wegrzyn J, Kuchenbauer F, Hirst M, Tohyama K, Humphries RK, Lam WL, Marra M, Karsan A. Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations. Blood. 2011 Jan 13;117(2):595-607. Authors proof
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.Authors Proof