Christiane . Ferran, M.D., Ph.D
Professor of Surgery
Division of Vascular Surgery
The Transplant Institute
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-370F/G
Boston, MA 02215
Office Phone: 617-632-0440
Office Fax: 617-632-0445
Christiane Ferran earned her MD from Saint Joseph School of Medicine in Beirut Lebanon in 1983, her Nephrology Board from University of Paris VI in Paris France in 1987, her masters in Immunology from Pasteur Institute in Paris France in 1988 and her PhD in Biochemistry and Immunology from University Paris VII in Paris France in 1992. She then completed a post-doctoral fellowship at the Beth Israel Deaconess Medical Center with Dr. Fritz H. Bach from 1993-1995. In 1995, Dr. Ferran joined the Division of Transplant Surgery as an Instructor then an Assistant Professor. In 1999, following the completion of a Nephrology fellowship at the Beth Israel Deaconess Medical Center, Dr Ferran was also appointed as Associate Professor in the Division of Nephrology, Department of Medicine and since holds a dual appointment in Surgery and Medicine at the Harvard Medical School. In 2005, Dr. Ferran joined the Division of Vascular Surgery, Department of Medicine at the Beth Israel Deaconess Medical Center and became a member of the CVBR. Dr. Ferran was promoted to Professor of Surgery in 2009.
Research Interests: Vascular Complications of Diabetes & Transplant Associated Arteriosclerosis.
Basic Research - The research interests of my laboratory are in the fields of vascular biology, micro and macrovascular complications of diabetes, liver regeneration, transplantation including islet transplantation and autoimmune diabetes.
Cytoprotective and homeostatic genes. The work in my laboratory is focused on the understanding of the function(s) of the cytoprotective genes A20, Bcl-2, Bcl-xL and A1 in different cell types, their relationship to the pathophysiology of diseases and their potential therapeutic use in atherosclerosis, organ transplantation, diabetes and hepatitis. This interest is based on our original finding that these genes serve a broad cytoprotective function in endothelial cells by shutting down inflammation through blockade of NF-?B as well as protecting from apoptosis.
Atheroprotective genes and the pathophysiology of macro and microvascular complications in diabetes mellitus. A20 serves an anti-atherogenic function in smooth muscle cells via inhibition of cell proliferation and induction of apoptosis in neointimal smooth muscle cells. A20 levels are decreased in diabetic patients and diabetic animals. A20´s decrease is due to unique glucose dependent post-translational O-glycosylation that act as a flag for subsequent ubiquitination and degradation in the proteasome. Loss of this important atheroprotective mechanism contributes to the molecular basis for increased risk of atherosclerosis in diabetic patients. A20 also demonstrate a potent anti-angiogenic function in retinal endothelial cells. Here again, diabetes related degradation of A20 would significantly contribute and aggravate heightened angiogenesis in diabetic retinopathy. In addition to its "atheroprotective" properties, A20 has important protective effects in other cell types.
Islet Transplantation. A20 retains in beta-cells its anti-apoptotic an anti-inflammatory potential and thus is an ideal candidate to genetically engineer islet grafts for the treatment of diabetes.
Liver regeneration and repair. A20 protects mice from lethality in models of acute toxic hepatitis, lethal radical hepatectomy and lethal liver ischemia reperfusion injury by promoting hepatocyte survival by shutting down apoptosis and necrosis through decreased expression of Caspase-8 and increased expression of PPAR alpha, containing inflammation through inhibition of NF-kappa B and unexpectedly promoting their proliferation by shutting down the cell cycle inhibitor: p21waf1. It is clear that these findings constitute a strong basis for the use of this protein in liver-directed gene therapy.
Clinical translation. The directions that we are taking should help us develop experimental models that will establish the therapeutic potential of these genes and set the basis for their use in clinical settings.
New and Noteworthy Publications:
Cooper JT, Stroka DM, Brostjan C, Palmetshofer A, Bach FH and Ferran C. A20 blocks endothelial cell activation through a NF-?B-dependent mechanism. Journal of Biological Chemistry, 1996, 271: 18068-18073. This paper encompasses the first demonstration of the potent and broad anti-inflammatory effect of A20 in endothelial cells through inhibition of the transcription factor NF-?B. This seminal work was reproduced by several other investigators as well as by our group in other cell types, confirming the ubiquitous anti-inflammatory function of A20 in all cell types tested so far.
Bach FH, Hancock WW and Ferran C. Expression of protective genes expressed in endothelial cells: A regulatory response to injury. Immunology Today, 1997, 18: 483-486. In this viewpoint published in Immunology Today, a new concept in endothelial cell biology is introduced to the scientific community suggesting that endothelial cells have a balancing component to their pro-inflammatory response to injury as they upregulate a set of protective genes, including anti-apoptotic and anti-inflammatory genes that serve to limit the activation process. thereby limiting injury.
Badrichani AZ, Stroka DM, Bilbao G, Curiel DT, Bach FH and Ferran C. Bcl-2 and Bcl-XL Serve an Anti-inflammatory Function in Endothelial Cells Through Inhibition of NF ?B.. J. Clin. Invest. 1999, 103: 543-553. In this work, we present the first evidence for a novel anti-inflammatory function of the prototypic bcl family members Bcl-2 and Bcl-xL in endothelial cells. This work was critical to the understanding of the molecular basis for maintaining homeostasis in the healthy endothelium.
Daniel S, Arvelo MB, Patel VI, Longo CR, Shrikhande G, Shukri T, Mahiou J, Sun DW, Mottley C, Grey ST, Ferran C. A20 protects from TNF, Fas and NK mediated cell death by inhibiting caspase 8 activation. Blood, 2004: 104:2376-2384. Data presented in this paper demonstrate for the first time that the anti-apoptotic effect of A20 is not limited to TNF-triggered apoptosis, as initially suggested. Rather, A20 affords broad endothelial cell protective functions by effectively shutting down both apoptotic and necrotic cell death pathways initiated by inflammatory and immune insults by inhibiting caspase 8 activation. Since this publication we have evidence that A20 binds and ubiquitinates pro-caspase 8, leading to its degradation. These results are under review in the J. Exp. Med.
Patel VI, Daniel S, Longo CR, Shrikhande G, Scali ST, Czismadia E, Groft C, Shukri T, Mottley-Dore C, Ramsey HE, Fisher MD, Grey ST, Arvelo MB, Ferran C. A20 a modulator of smooth muscle cell proliferation and apoptosis, prevents and cures neointimal hyperplasia. The FASEB Journal, 2006, 20: 1418-1430. In this paper, we report that A20 not only maintains its potent NF-?B inhibitory function in smooth muscle cells, blocking the expression of the pro-atherogenic proteins ICAM-1 and MCP-1, but also inhibits smooth muscle proliferation via increased expression of the Cyclin-dependent kinase inhibitors p21waf1 and p27kip1. In addition, A20 unexpectedly sensitizes intimal SMC to apoptosis by increasing the generation of nitric oxide. These opposing anti and pro-apoptotic effects of A20 in EC and SMC are critical for the prevention and regression of intimal hyperplasia. These data represent the first in vivo proof for the effect of A20 upon vascular remodeling further strengthening our pursuit of A20 as a therapeutic candidate for the treatment of intimal vascular disease including atherosclerosis, macrovascular complications of diabetes, restenosis post-angioplasty and transplant arteriosclerosis. It is our hypothesis that protection from atherosclerosis will best be achieved by containing inflammation, promoting death of smooth muscle cells in the neointima while protecting endothelial cells.