Christiane J. Ferran, MD, PhD

Lewis Thomas Professor of Surgery, Harvard Medical School


 

Ferran-Christiane

Research Group

Erin Driscoll
Kevin Elkhoury
Cleide Gonçalves da Silva, PhD
Philip LoGerfo
Erin McIntosh, MD
Marianna Pavlyha
Jesus Revuelta-Cervantes, PhD

Research Focus

My laboratory focuses on:

  • Defining the molecular signature of what “return to homeostasis” entails in the face of injury, whether inflammatory, immune, infectious, metabolic, or mechanical
  • Identifying the culprits that hinder “return to homeostasis,” resulting in pathology
  • Validating signature molecules in animal models of human disease for potential clinical translation as diagnostic, prognostic, and therapeutic tools

This line of research was triggered by our seminal discovery that up-regulation of the ubiquitin-editing protein A20 or the anti-apoptotic Bcl member, A1, in endothelial cells in response to inflammatory stimuli, serves a general “protective” function by shutting down inflammation through inhibition of the transcription factor NF-B (JBC 1996;271:18068). Subsequent studies confirmed A20 as one of humans’ most potent and ubiquitous physiologic anti-inflammatory molecules. A20 not only goes to the NF-B heart of inflammation, but also beyond to control IFN gamma and alpha/beta signaling, and modulate cell survival and proliferation, with return to homeostasis as the ultimate goal. We established the therapeutic benefits of A20-based therapies in a number of animal models of human diseases that share inflammation as a central pathogenic component, mainly in the three fields listed below.

Vascular diseases

Our data qualifies a potent “atheroprotective” and novel anti-angiogeneic function of A20 in animal models of:

  • Neointimal hyperplasia post-balloon angioplasty
  • Transplant arteriosclerosis, the main cause of failure of vascularized allografts
  • Accelerated atherosclerosis of diabetes
  • Vein graft and prosthetic arterial graft failure
    proliferative retinopathies, namely retinopathy of prematurity and diabetic retinopathy
Liver regeneration and repair

We have also extensively established a potent “hepatoprotective” role for A20 in the liver, stemming from combined anti-inflammatory, anti-apoptotic, and pro-proliferative functions of A20 in hepatocytes. Accordingly, A20-based therapies protect mice from lethality in models of acute chemically-induced toxic hepatitis, lethal radical hepatectomy where 90% of the liver is resected, prolonged warm liver ischemia, and orthotopic liver transplantation using marginal livers.
 
Additionally, we uncovered an unsuspected phenotype in A20 heterozygous mice, whereby a benign 2/3 hepatectomy causes a staggering 50% lethality. These data have important clinical implications. Indeed, single nucleotide polymorphisms that negatively impact A20 expression and/or function should be recognized in order to gauge safety of extensive liver resections for donation or tumor.

We also recently discovered that A20 regulates lipid metabolism in a way that improves fatty liver disease in a mouse model of human non-alcoholic fatty liver disease.

Current pre-translational studies in pigs using clinically safe viral vectors to specifically induce A20 expression in the liver are very promising and prelude clinical implementation.

Treatment of diabetes

Islet Transplantation: A20 retained its anti-apoptotic and anti-inflammatory functions in β-cells, thus was an ideal candidate to genetically engineer islet grafts for the treatment of diabetes.

Insulin alternatives: Recently, we uncovered a novel anti-diabetic function of A20, whereby hepatic overexpression of A20 in a mouse model of type I diabetes restored glycemic control in an insulin independent manner. We are characterizing the molecular basis of this novel function of A20 and exploring its potential use as an anti-diabetic therapy in both type I and type II diabetes.

Accomplishments 2016-2017

Administrative
  • Member of the Promotion, Appointment, and Reappointment Committee, Harvard Medical School (HMS)
  • Member of the Committee for Senior appointment (COSA), BIDMC
  • Member of the Promotion and reappointment Committee, Department of Surgery, BIDMC
  • Member of the search committee for Scientific Director of the Transplant Center, Massachusetts General Hospital, HMS
  • Member of the search committee for Chief of Urology, BIDMC, HMS
  • Member of the search committee for Chief Academic Officer, BIDMC
  • Member of the executive committee of the Center for Vascular Biology Research, BIDMC
Scientific review board
  • Reviewer for the NIH ZEB-OSR-C (O1) study section Multiscale Modeling (MSM) Program
  • Reviewer for the NIH Surgery Anesthesia Traumatology (SAT) study section
  • Reviewer for the Fund for Scientific Research-FNRS, Brussels, Belgium
  • Reviewer for the Swiss National Science Foundation, Zurich, Switzerland
Invited presentations and visiting professorships
  • “What returns to vascular homeostasis entails,” Lebanese American University, Beirut, Lebanon
  • “Novel technologies to revolutionize transplantation,” Lebanese American University, Beirut, Lebanon
  • “Prometheus Myth under A20 fire… A Tale of Discovery and Translation in Liver Regeneration and repair,” Transplantation Grand Rounds, the Transplant Institute, Medical University of Virginia, UVA, Charlottesville, VA
  • “A20 and vascular homeodynamics: a tale of discovery and translation,” Renal Grand Rounds, Brigham and Women’s Hospital, HMS, Boston MA
  • “An A20 suite: Insulin no longer in diabetes,” Mass Biologics Seminar Series, University of Massachusetts Medical School, Mattapan, MA
  • “A20 and vascular homeodynamics: a tale of discovery and translation,” Molecular Medicine Series, Molecular Cardiology Research Institute (MCRI), Tufts Medical School, Boston, MA 
Awards
  • Christiane Ferran, MD, PhD: Avicenna Award in Health and Medical Sciences, Harvard Arab Alumni
  • Jesus Revuelta-Cervantes, PhD: Abstract selected for oral presentation at the Clowes Visiting Professorship competition for his work on A20 and fatty liver diseases
  • Brandon Wojcik, MD: Selected for oral presentation at the Harvard Surgery Research Day competition for his work on A20 and incidence/severity of thrombotic venous diseases
Patents

PCT/US2017/046938, international # WO 2018/035121 A1. “Novel therapies to achieve glycemic control.” Inventors: Christiane Ferran MD, PhD, Cleide da Silva, PhD, and Alessandra Mele, MD

Teaching, Training, and Education

For the past 20 years I have been training post-doctoral research fellows, surgical residents, undergraduate, graduate, and medical students, and research associates who rotate in my laboratory. I also mentor junior faculty in the Department of Surgery and the Center for Vascular Biology Research. Speaking to my commitment to teaching/mentoring, I serve on four NIH-funded T32 and one T35 training grants as:

  • Co-director of the Longwood-Harvard T32 in vascular surgery (Director: Frank LoGerfo, MD,  BIDMC)
  • Faculty mentor in the Harvard trauma inflammation T32( Director: Wolfgang Junger, PhD, BIDMC)
  • Faculty mentor in the renal T32 (Director: Martin Pollak, MD, BIDMC)
  • Faculty mentor in the transplantation biology T32 (Director: Joren Madsen, MD, MGH)
  • Faculty mentor in the in vascular surgery T35 (Director: Frank LoGerfo, MD, BIDMC)

Selected Research Support

  • Novel therapies to achieve glycemic control; Juvenile Diabetes Research Foundation, 2016-2019; PI: Christiane Ferran, MD, PhD. (Co-investigator: Cleide G. da Silva, PhD)
  • Bioengineering of vein graft to resist intimal hyperplasia; NIH, 2018-2020. PI: Christiane Ferran MD, PhD. (Co-investigator: Mauricio Contreras, MD)
  • Mechanisms of prosthetic arterial graft failure; NIH, 1987-2021; PIs: Christiane Ferran MD, PhD; Frank W. LoGerfo, MD, David Mooney, PhD
  • Genetic engineering of vein bypass grafts in vascular and cardiovascular surgery, NIH, 2007-2018; Co-PI: Christiane Ferran, MD, PhD ( Contact PI: Frank W. LoGerfo, MD)

Selected Publications

Moll HP, Lee A, Peterson CR, Cervantes JR, Wojcik BM, Parulkar A, Mele A, LoGerfo PJ, Siracuse JJ, Csizmadia E, da Silva CG , Ferran C. A20 haploinsufficiency aggravates transplant arteriosclerosis in mouse vascular allografts: Implications for clinical transplantation. Transplantation 2016;100(11):e106-e116.

LoGerfo PJ, Revuelta Cervantes JM, Mele A, Neidich A , Amr S, Chien V, Wojcik BM, da Silva CG, Ferran C,  and Cooper JT. Donor and recipient polymorphisms in theTNFAIP3 (A20) gene correlate with risk of acute rejection and predict long term function in renal allografts. 2017;Submitted Nephrology, Dialysis, Transplantation.

da Silva CG, Kaczmarek E, Essayagh S, Daniel S, Choi L, Arvelo M, Wojcik BM, Patil M, Vora D, Moll HP, Ferran C.  A20 increases eNOS transcription in an ERK5/KLF2 dependent manner to sustain endothelial cell function in the face of inflammatory insults. 2017; Submitted.