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Vascular Medicine Institute

VMI

Jeffrey Isenberg, M.D., M.P.H.

Isenberg

Associate Professor of Medicine
Pulmonary, Allergy and Critical Care Medicine

E1258 BST
200 Lothrop Street
Pittsburgh, PA 15261

Phone:412-383-5424
Fax: 412-648-3046
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

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.

signaling

 

Regulation of NO/cGMP signaling by thrombospondin-1 (TSP1) in vascular cells. Our work has demonstrated that ligand receptor interaction between the secreted protein thrombospondin-1 and its cognate receptor CD47 constantly and redundantly regulates the canonical NO pathway, inhibiting eNOS activation, and also inhibiting directly the downstream NO target sGC and the cGMP activated protein kinases. More recent work has found that TSP1 can limit the pro-angiogenic and NO based activity of VEGF by disrupting the constitutive binding/interaction of VEGFR2 and CD47. The inhibitory ligand receptor signal between TSP1 and CD47 functions in vivo to inhibit vasodilation, decrease tissue survival and blood flow in ischemia and ischemia-reperfusion, and can elevate blood pressure. Conversely, disrupting the TSP1-CD47 signal increases the beneficial effects of NO to increase blood flow, limit platelet aggregation and lower blood pressure.

Key Publications

Yao M, Roberts DD, Isenberg JS. (2011) Thrombospondin-1 inhibition of vascular smooth muscle cell responses occurs via modulation of both cAMP and cGMP. Pharmacol Res. 63(1):13-22.

Kaur S, Martin-Manso G, Pendrak ML, Garfield SH, Isenberg JS, Roberts DD. (2010) Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47. J Biol Chem. 285(50):38923-32.

Bauer EM, Qin Y, Miller TW, Bandle RW, Csányi G, Pagano PJ, Bauer PM, Schnermann J, Roberts DD, Isenberg JS. (2010) Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation. Cardiovasc Res. 88(3):471-81.

Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, DeGraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD. Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling. Sci Transl Med 1, 3ra7 (2009).

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 Lab

Pubmed link

Recognition

Dr. Isenberg's work in radiation biology was recognized by the Cancer Research Center of the National Cancer Institute as among the "top scientific advances" for 2010.

Dr. Isenberg's research in the world media

Dr. Isenberg informed an article by Newsweek about turning research discoveries into therapeutic advances.

A publication in 2009 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  
ITxM
ITXM ITxM
HCWO
HCWP
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