- ASSOCIATE PROFESSOR Developmental and Regenerative Biology
- ASSOCIATE PROFESSOR Medicine
M.D., Universite de Paris XII, Paris, France
Ph.D., University of British Columbia, Vancouver, B.C., Canada
Clinical Scientist, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology
MSc., Universite de Paris XII, Paris, France
Research Foundation New Investigator Award
Irma Hirschl/Weill-Caulier Trust Research Award
Roche Foundation for Anemia Research (RoFAR) Award
Black Family Stem Cell Institute Exploratory Research Award
American Cancer Society
NIH Mentored Clinician Scientist Career Award
National Cancer Institute
1991 - 1995
Terry Fox Physician-Scientist Fellowship
National Cancer Institute of Canada
My Laboratory is focused on elucidating signals that regulate transcriptional programs of stem cell fate decisions and mechanisms of alterations of these in disease.
Stem cells have a unique and remarkable property in that a single cell can regenerate the entire tissue (somatic) or all tissues in the whole body (embryonic). A central focus of my laboratory is to dissect molecular mechanisms that regulate stem cell fate with critical implications for understanding and treatment of human disease. We work with both embryonic stem (ES) cells and adult hematopoietic (blood) stem cells and use transgenic and knock out mouse models. Located in hypoxic niches, adult hematopoietic stem cells are mostly quiescent whereas embryonic stem cells are highly proliferative. We have identified distinct members of Forkhead FoxO family of transcription factors as critical regulators of stem cell activity in adult hematopoietic and in embryonic stem cells. FoxO factors are bona fide tumor suppressors with key functions in the regulation of longevity and metabolism. The targets of FoxO in stem cells that we have identified are key regulators of pluripotency of (ES) or of quiescence and genomic stability of (adult) stem cells. Our current work involves investigating the metabolic regulation and function of FoxO in normal and cancer stem cells. These investigations should generate information that can be exploited for improving the expansion of normal stem cells for therapy and for the specific targeting of cancer stem cells.
Red blood cells carry oxygen to all tissues in the body and the alteration in their production or maturation causes disorders such as b-thalassemia and sickle cell anemia. Another focus of my laboratory has been to elucidate signaling pathways that control the production and maturation of red blood cells. Work in the laboratory has found important functions for AKT signaling pathway in these processes. Using genetic approaches we are addressing the function of AKT phosphorylation of its downstream targets GATA-1 and Foxo3 in vivo. Our unpublished results indicate that this pathway might be exploited for the treatment of some human erythroid disorders.
We have recently identified a novel regulator of human ES cell pluripotency. The potential of this factor in improving the efficiency of generation of induced pluripotent stem (iPS) cells is being currently tested in the laboratory.
Using, genetic, biochemical and molecular approaches my laboratory is investigating questions related to stem and progenitor cell fate. In carrying this work forward we have set up multiple collaborations with investigators at Mount Sinai and elsewhere. Several projects deriving from the line of work described here are available to PhD and MD/PhD students at Mount Sinai.
Xin Zhang M.D.-Ph.D., Post-doctoral Fellow
Pauline Rimmelé Ph.D., Post-doctoral Fellow
Valentina D’Escamard, MSc., Laboratory Manager
Carolina Bigarella Ph.D., Post-doctoral Fellow
Genís Campreciós Ph.D., Post-doctoral Fellow
Jose Luis Garrido, MSc., Associate Researcher
Brigitte Izac, MSc., Visiting Researcher (INSERM Paris)
Sébastien Lofek, Visiting Student (Université de Paris VII)
Adithya Sarveswaran, High School Student in Training
Zhang X, Yalcin S, Lee DF, Lee S, Yeh T, Jie S, Kennedy M, Sellers R, Landthaler M, Tuschl T, Chi NW, Lemischka I, Keller G, Ghaffari S. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nature Cell Biology 2011 July;: doi:10.1038/ncb2293.
Yalcin S, Marinkovic D, Mungamuri S, Tong W, Ghaffari S. Oxidative stress-mediated amplification of AKT/mTOR signaling pathway leads to myeloproliferative syndrome in Foxo3-/- mice . EMBO Journal 2010 Nov 26; 29(24): 4118-31.
Yu D , dos Santos CO, Zhao G, Jiang J, Amigo JD, Khandros E , Dore LC, Yao Y, D'Souza J, Ghaffari S, Choi J, Friend S, Tong W, Orange JS, Paw BH, Weiss MJ. miR-451 Protects Against Erythroid Oxidant Stress by Repressing 14-3-3z.. Genes & Development 2010; 24(15): 1620-1633.
Zhang X, Rielland M, Yalcin S, Ghaffari S. Regulation and function of FoxO transcription factors in normal and cancer cells. What have we learned?. Current Drug Targets [Epub ahead of print] 2011 Mar 28;.
Shazib P, Ghaffari S, Taneja R. Oxidative Stress Regulation of Stem and Progenitor Cells. Forum Issue Antioxidants & Redox Signaling 2009; 11(11): 2777-2789.
Yalcin S, Chung TK, Vercherat C, Gulbagci J, Gopinadhan S, Taneja R, Ghaffari S. Stra13 Regulates oxidative stress mediated skeletal muscle degeneration. Hum Mol Genet 2009; 18(22): 4304-4316.
Yalcin S, Zhang X, Marinkovic D, Luciano J, Sarkar A, Ghaffari C, Vercherat C, Taneja R, Ghaffari S. Foxo3 is essential for the regulation of ATM and oxidative stress-mediated homeostasis of hematopoietic stem cells. Journal of Biological Chemistry 2008; 283: 25692-25705.
Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Forum Issue Antioxidants & Redox Signaling 2008; 10: 1923-1940.
Marinkovic D, Zhang X, Yalcin S, Brugnara C, Huber T, Ghaffari S, . Foxo3 is required for the regulation of oxidative stress in erythropoiesis. Journal of Clinical Investigation (This paper was highlighted in Conmentary: JCI (8): 2075-2077, 2077). 2007; 117(8): 2133-2144.
Zhao W, Kitidis C, Fleming MD, Lodish HF, Ghaffari S , . Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase-AKT signaling pathway. Blood (this paper was highlighted in Inside Blood; 107 (3): 851-85) 2006; 107(3): 907-915.
Ghaffari S, Kitidis C, Zhao W, Marinkovic D, Fleming MD, Luo B, Marszalek J, Lodish HF. AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation. Blood Mar 1; 107(5): 1888-91.
Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 2003; 100(11): 6523-6528.
Steen H, Fernandez M, Ghaffari S, Pandey A, Mann M. Phosphotyrosine mapping in oncogenic BCR-ABL using phosphotyrosine-specific immonium ion scanning. Molecular Cell Proteomics 2003 Mar; 2(3): 138-45.
Zhao X, Ghaffari S, Lodish HF, Malashkevich VN, Kim PS. Stucture of the BCR-ABL oncoprotein oligomerization domain. Nature Structural Biology 2002 ; 9(2): 1-4 .
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Ghaffari did not report having any of the following types of financial relationships with industry during 2014 and/or 2015: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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