Department of Medicine

University of Pittsburgh

Jeffrey Isenberg, MD, MPH

Associate Professor
7017 BST 3
3501 Fifth Avenue
Pittsburgh, PA 15260

Phone: 412-383-5424
Fax: 412-648-7223
Email: jsi5@pitt.edu

Bio

Dr. Isenberg earned his Bachelor’s at the University of Pennsylvania and completed his medical training at Tulane University School of Medicine, where he simultaneously earned a Masters of Public Health. He interned at Roosevelt-St. Luke’s Hospital and completed general surgery training at Staten Island University Hospital. He further specialized in reconstructive, hand and microsurgery with fellowship training at Yale University, the University of Connecticut and the University of Southern California. He then completed a post-doctoral research fellowship in the Laboratory of Pathology of the NCI, NIH funded by a Cancer Research Fellow Training Award.

Research Interests

Dr. Isenberg's research interests have centered on the need to enhance tissue blood flow, perfusion and wound healing, and stem from his background as a reconstructive microsurgeon. As a clinician, the focus of his work was the development and application of novel autologous composite tissue units for closure of complex wounds. In addition to anatomical research in tissue vascular anatomy, he studied the ability of complex tissue reconstructive units to withstand stress injuries. This enabled him to improve the clinical range of these surgical approaches. However, limitations with clinical results achievable via surgical interventions alone motivated him to focus purely on research. He now studies the molecular aspect of blood flow and perfusion, and has recently discovered a novel inhibitory pathway that blocks physiologic nitric oxide (NO) signaling. NO is one of the body's central means of promoting blood flow through its ability to dilate arteries, improve cardiac contractility and decrease platelet interactions and clotting. Recently he made the startling discovery that a matrix protein, thrombspondin-1 (TSP1), completely inhibits NO-driven events in vascular cells by blocking activation of sGC. This process requires the interaction of TSP1 with the cell surface receptor CD47. He has found that this inhibitory pathway limits NO signaling both in cells and in vivo. In turn, by blocking this pathway it is possible to enhance NO signaling, thereby increasing tissue blood flow and perfusion, survival to ischemia and I/R injury, and preventing platelet thrombosis.

The Doppler movies below demonstrate TSP1, via CD47, acutely regulating blood flow changes under vasoactive stress. It shows random cutaneous flaps that face a fixed degree of ischemic challenge undergoing rapid loss of blood flow. In contrast, similar flaps in TSP1 or CD47 null animals show no significant change in blood flow.

Wild Type
CDC 47 Null
TSP1 Null

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Ongoing areas of interest include the implications of this new paradigm in relation to blood pressure and cardiac function. Additionally, he examines the cell and tissue protective effects arising from targeting CD47. He has recently found this receptor critical in preventing tissue damage from radiation injury.

Regulation of NO/cGMP

Regulation of NO/cGMP signaling by thrombospondin-1 (TSP1) in vascular cells.  VEGF signaling through its receptor activates the kinase Akt, which phosphorylates eNOS on Ser1179 which in turn increases nitric oxide (NO) synthesis.  NO activates sGC to increase cGMP synthesis.  cGMP acts on several downstream target in vascular cells to stimulate a number of pro-survival events.  In stimulating blood vessel relaxation NO directly increases tissue and organ blood flow. At physiological concentrations, TSP1 acts primarily through its receptor CD47 to limit sGC activation.  At nM concentrations, TSP1 also signals through CD36 to inhibit the same responses, but CD47 is also necessary for these signals to inhibit cGMP signaling.  Therefore, engaging either receptor is sufficient to inhibit NO/cGMP signaling, but CD47 is the necessary receptor of TSP1 action. Targeting TSP1-CD47 with agents that block this inhibitory pathway enhances NO signaling and increases angiogenesis, tissue survival to ischemia and blood flow.

Key Publications

Isenberg JS, Maxhimer JB, Powers P, Tsokos M, Frazier WA, Roberts D. Treatment of liver ischemia– reperfusion injury by limiting thrombospondin-1/CD47 signaling. Surgery. 2008;144(5):752-761

Isenberg JS, Maxhimer JB, Hyodo F, Pendrak ML, Ridnour LA, DeGraff WG, Tsokos M, Wink DA, Roberts DD. Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. Am J Pathol. 2008 Oct;173(4):1100-12. Epub 2008 Sep 11.

Isenberg JS, Romeo MJ, Maxhimer JB, Smedley J, Frazier WA, Roberts DD. Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease. Ann Surg. 2008 May;247(5):860-8.

Isenberg JS, Romeo MJ, Yu C, Yu CK, Nghiem K, Monsale J, Rick ME, Wink DA, Frazier WA, Roberts DD. Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling. Blood. 2008 Jan 15;111(2):613-23.

Isenberg JS, Romeo MJ, Abu-Asab M, Tsokos M, Oldenborg A, Pappan L, Wink DA, Frazier WA, Roberts DD. Increasing survival of ischemic tissue by targeting CD47. Circ Res. 2007;100(5):712-720.

Isenberg JS, Hyodo F, Matsumoto K, Romeo MJ, Abu-Asab M, Tsokos M, Kuppusamy P, Wink DA, Krishna MC, Roberts DD. Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Blood. 2007 Mar 1;109(5):1945-52.

Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD. CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J Biol Chem. 2006 Sep 8;281(36):26069-80.

Isenberg JS, Wink DA, Roberts DD.Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses. Cardiovasc Res. 2006 Sep 1;71(4):785-93.

Isenberg JS, Ridnour LA, Perruccio EM, Espey MG, Wink DA, Roberts DD. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13141-6.

Pubmed link

News

Dr. Isenberg's research in the world media

A recent publication by Dr. Isenberg has drawn the attention of worldwide media.

An interview with Dr. Isenberg can be heard here, and links to related articles from various media sources are below:

USA
Europe
Asia
Science Daily EFE (Spanish news agency) Asia One
MSN Health El Periodico (Spain) The Straits Times (Singapore)
US News Index (Hungary)  
Reuters Hirado (Hungary)  
Pittsburgh Tribune Review The Daily Telegraph (UK)  
WMBF News The Irish Independent News  
Gant Daily News Cancer Research UK  
  Tovima (Greece)  
  Wissenshaft Aktuell (Germany)  
  Russia Today