Steven D. Freedman

Department of Medicine
Beth Israel Deaconess Medical Center
Dana Building, Room 552-East Campus
330 Brookline Avenue
Boston, MA 02215
Tel: (617) 667-5576
Fax: (617) 667-0536
Email: sfreedma@bidmc.harvard.edu

My laboratory is translationally based with strong basic science and clinical research components. The two areas of focus are determination of 1) the mechanism(s) of inflammation in Cystic Fibrosis and chronic pancreatitis and 2) the mechanism and treatment of refractory visceral pain in these diseases.

Understanding the Mechanism by which Cystic Fibrosis Gene Mutations Lead to Disease
Our genetic studies have shown that 50% of patients with idiopathic chronic pancreatitis have mutations in the cystic fibrosis (CFTR) gene. To understand how these mutations lead to the phenotypic expression of disease, our group has demonstrated that CFTR dysfunction leads to a defect in fatty acid metabolism in CF affected organs using transgenic mouse strategies. Correction of this abnormality reversed the pathologic changes in the pancreas, ileum, as well as Pseudomonas induced lung inflammation. The same fatty acid defect was confirmed in humans with CF, demonstrated a CFTR gene dosing effect, and has led to the first clinical trial. Current projects include defining the mechanism by which CFTR dysfunction directly alters fatty acid biosynthetic enzymes, the role of PPAR’s in this process, and the identification of modifier genes.

Cortical Dysfunction as the Mechanism for Refractory Visceral Pain
The other focus of my lab is on visceral pain mechanisms and the development of novel treatment strategies. In collaboration with Alvaro Pascual-Leone MD, PhD, our groups have identified the site within the brain representing pain from chronic pancreatitis. We hypothesized that this region, referred to as SII in the right side of the brain, is dysregulated in chronic abdominal pain syndromes such as chronic pancreatitis and results in refractory pain. We have demonstrated that inhibition of SII using Transcranial Magnetic Stimulation (TMS) reduces pain and appears to regulate the release of inflammatory mediators targeted to the pancreas. Current projects include: an NIH funded double-blind, sham controlled trial of TMS in the treatment of refractory abdominal visceral pain and its effect on modulation of cytokine and chemokine responses; identification of the neurotransmitters responsible for pain perception in SII using MR Spectroscopy and its modulation by TMS; and identification of cortical pathways leading to the regulation of the innate immune response through activation of SII.

References:

• Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, and Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr-/- mice. Proc. Natl. Acad. Sci. 1999, 96:13995-14000.
• Sheth S, Shea J, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui L-C, Durie PR, Zielenski Z, and Freedman SD. Association of Primary Sclerosing Cholangitis with Mutations of the Cystic Fibrosis Gene. Human Genetics 2003, 113:286-292.
• Freedman SD, Blanco PG, Zaman MM, Shea J, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, and O’Sullivan BP. Association of Cystic Fibrosis With Abnormalities In Fatty Acid Metabolism. New Engl. J. Med, 2004; 350:560-569.
• Fregni F, Freedman SD, and Pascual-Leone A. Recent advances in the treatment of chronic pain with noninvasive brain stimulation techniques. Lancet Neurology 2007; 6:188-191.