Jeffrey Isenberg, MD, MPH
Associate Professor of Medicine
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.
Department of Medicine
Division of Pulmonary, Allergy and Critical Care Medicine
7017 BST 3
3501 Fifth Avenue
Pittsburgh, PA 15260
Office Telephone: 412-383-5424
Lab Telephone: 412-648-7223
Clinical ExpertiesI trained in general surgery with an internship at St. Luke's-Roosevelt Hospital, NYC and residency at Staten Island University Hospital. NYC I did a residency in reconstructive and hand surgery at Yale-New Haven Hospital. I did a fellowship in microvascular surgery at the University of Southern California. Presently I do research only.
Research ExpertiesMy laboratory's focus is on signal transduction pathways that control blood flow and cellular/tissue responses to stress. Several years ago we discovered that a matrix protein thrombopsondin-1 (TSP1), on interacting with its high affinity cell receptor, CD47, potently inhibits the canonical nitric oxide (NO) signaling pathway. At the level of platelets, TSP1, via CD47, potently limits the anti-aggregatory activity of NO. We have since discovered the TSP1-CD47 axis also inhibits cAMP and VEGF signaling, while at the same time promoting programmed cell death. Therapeutic blockade of TSP1-CD47 increases blood flow in the presence of ischemia, ischemia-reperfusion, advanced age and in murine, rat and porcine models of peripheral vascular disease. My lab is exploring the pathobiolgy of CD47 and has, in collaboration with NIH colleagues, written the Nature Molecular Signaling Gateway pages on non-human and human CD47. Current projects in the laboratory include work in pulmonary hypertension, left ventricular heart failure, ischemia reperfusion injury, renal transplant modulation, sickle cell disease and cellular regeneration as applied to tissue engineering. Our team is part of a unique ex vivo functional lung and vascular core that leverages explanted lungs from patients undergoing transplant to obtained functional data at multiple levels including cell, tissues, vessels and whole organ and further allows for early testing of novel therapeutics in these human organs.
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 signaling by thrombospondin-1 (TSP1) in vascular cellsVEGF 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.
Selected PublicationsView Dr. Isenberg's publications on PubMed
- Bauer PM, Bauer EM, Rogers NM, Yao M, Feijoo-Cuaresma M, Pilewski JM, Champion HC, Calzada MJ, Isenberg JS. Activated CD47 Promotes Pulmonary Arterial Hypertension Through Targeting Caveolin-1. Cardiovascular Research. 2012 Mar 15;93(4):682-93. Editorialized: Thrombospondin-1 in pulmonary arterial hypertension: what ails NOS? Chan WP, Horowitz JD. Cardiovasc Res. 2012 93(4): 540-542.
- Novelli EM, Kato GJ, Ragni MV, Zhang Y, Hildesheim ME, Nouraie M, Barge S, Meyer MP, Hassett AC, Gorduek VR, Gladwin MT, Isenberg JS. Plasma Thrombospondin-1 is Increased During Acute Sickle Cell Vaso-occlusive Events and Associated with Acute Chest Syndrome, Hydroxyurea Therapy and Lower Hemolytic Rates. Am J Hematol. 2012 Mar;87(3):326-30
- Roger NM, Thomson AW, Isenberg JS. Activation of Parenchymal CD47 Promotes Renal Ischemia-Reperfusion Injury. Journal of the American Society of Nephrology. 2012 Sep;23(9):1538-50. Highlighted: Basic research: CD47 blockade may prevent renal ischemia-reperfusion injury. Nat Rev Nephrol Sep;23(9):1538-50. Highlighted: Activation of parenchymal CD47 promotes renal ischemia-reperfusion injury. Kidney International 2012 82, 943-944
- Csanyi G, Yao M, Rodriguez AI, Al Ghouleh I, Sharifi-Sanjani M, Frazziano G, Huang X, Kelley EE, Isenberg JS, Pagano PJ. Thrombospondin-1 Regulates Blood Flow via CD47 Receptor-Mediated Activation of NADPH Oxidase 1. Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):2966-73
- Roberts DD, Miller TW, Rogers NM, Yao M, Isenberg JS. The Matricellular Protein Thrombospondin-1 Globally Regulates Cardiovascular Function and Responses to Stress via CD47. Matrix Biol. 2012 Apr;31(3):162-9
- Rogers NM, Robert DD, Isenberg JS. Age-Associated Induction of Cell Membrane CD47 Limits Basal and Temperature-Induced Changes in Cutaneous Blood Flow. Annals of Surgery. 2013 Jul;238(1):184-91.
- Kaur S, Soto-Pantoja DR, Stein EV, Lui C, Elkahloun, AG, Pendrak ML, Nicolae A, Singh SP, Nie1 Z, Levens D, Isenberg JS, Roberts DD. Thrombospondin-1 Signaling Through CD47 Inhibits Self-Renewal by Regulating c-Myc and Other Stem Cell Transcription Factors. Sci Rep. 2013 Apr 17;3:1673
- Allen RA, Wu W, Yao M, Dutta D, Duan X, Bachman TB, Champion HC, Stolz DB, Robertson AM, Kim K, Isenberg JS, Wang Y. Nerve Regeneration and Elastin Formation Within Poly(glycerol sebacate)-Based Synthetic Arterial Grafts One-Year Post-Implantation in a Rat Model. Biomaterials. 2013 Oct 9. doi:pii: S0142-9612(13)01181-2
- Novelli EM, Kato GJ, Hildesheim ME, Barge S, Meyer MP, Hassett AC, Ragni MV, Isenberg JS, Gladwin MT. Thrombospondin-1 Inhibits ADAMTS13 Activity in Sickle Cell Disease. Haematologica. 2013 Nov;98(11):e132-4
- Rogers NM, Yao M, Sembrat J, George MP, Knupp H, Ross, MA, Sharifi-Sanjani M, Milosevic J, St. Croix C, Rajkumar R, Frid NM, Hunter KS, Mazzaro L, Novelli EM, Stenmark KR, Galdwin MT, Champion HS, Isenberg JS. Cellular, Pharmacological and Biophysical Evaluation of the Explanted Lungs From a Patient With Sickle Cell Disease and Severe PAH. Pulmonary Circulation. 2013. Dec; 3:936-951
- Rogers NM, Isenberg JS, Thomson AW. Plasmacytoid Dendritic Cells: No Longer an Enigma, and Now Key to Transplant Tolerance? American Journal of Transplantation. Am J Transplant. 2013 May;13(5):1125-33
- Soto-Pantoga DR, Stein EV, Rogers NM, Sharifi-Sanjani M, Isenberg JS, Roberts DD. Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opinions on Therapeutic Targets. 2013 Jan;17(1):89-103
- Rogers NM, Yao M, Novelli NN, Thomson AW, Roberts DD. Isenberg JS. Activated CD47 Regulates Multiple Vascular and Stress Responses: Implications for Acute Kidney Injury and Management. Am J Physiol Renal Physiol 2012 Oct;303(8):F1117-25
- Yao M, Rogers NM, Csanyi G, Rodriguez AI, Ross MA, St. Croix C, Knupp H, Novelli NM, Thompson AW, Isenberg JS. Thrombospondin-1 Activation of SIRP-? Stimulates ROS Production and Promotes Renal Ischemia Reperfusion Injury. J Am Society Nephrology. ASN.2013040433; published ahead of print February 7, 2014, doi:10.1681/ASN.2013040433
- Wang JM, Isenberg JS, Billiar TR, Chen AF. Thrombospondin-1/CD36 Pathway Contributes to Bone Marrow-Derived Angiogenic Cell Dysfunction in Type 1 Diabetes via Sonic Hedgehog Pathway Suppression. Am J Physiol Endocrinol Metab. J Biol Chem. 2014 Jan 8. [Epub ahead of print]
- Zimmerman MW, McQueeney KE, Isenberg JS, Pitt BR, Wasserloo KA, Homanics GE, Lazo JS. PTP4A3 phosphatase promotes VEGF signaling and stimulates SRC activation and endothelial cell motility. J Biological Chemistry. J Biol Chem. 2014 Jan 8. [Epub ahead of print]
- Sharifi-Sanjani M, Shoushtari AH, Quiroz M, Baust J, Sestito SF, Mosher M, McTiernan CF, St. Croix, CM, Champion HC, Isenberg JS. Cardiac CD47 Drives Left Ventricular Heart Failure Through Ca2+-CaMKII Regulated Induction of HDAC3. Journal of the American Heart Association. 2014 Jun 10;3(3). pii: e000670. PMID: 24922625
- Soto-Pantoja DR, Shiha HB, Maxhimera JB, Cook KL, Ghosha A, Isenberg JS, Roberts DD., Thrombospondin-1 and CD47 Signaling Regulate Healing of Thermal Injury in Mice. Matrix Biology. 2014 May 16. pii: S0945-053X(14)00087-0. doi: 10.1016/j.matbio.2014.05.003. [Epub ahead of print]
- Rogers NM, Sharifi-Sanjani M, Csányi G, Pagano PJ, Isenberg JS. Thrombospondin-1 and CD47 Regulation of Cardiac, Pulmonary and Vascular Responses in Health and Disease. Matrix Biology. Matrix Biol. 2014 Jan 10. pii: S0945-053X(14)00003-1. doi: 10.1016/j.matbio.2014.01.002. [Epub ahead of print]
- Rogers NM, Seeger F, Garcin ED, Roberts DD, Isenberg JS. Regulation of Soluble Guanylate Cyclase by Matricellular Thrombospondins: Implications for Blood Flow. Front Physiol. 2014 Apr 4;5:134. eCollection 2014. PMID: 24772092
- Kutten JC, McGovern D, Hobson CM, Luffy SA, Nieponice A, Reynolds SD, Isenberg JS, Gilberts T. Decellularized Tracheal Extracellular Matrix Supports Epithelial Migration, Differentiation and Function. Tissue Engineering Part A. In press June 6, 2014.
- Isenberg J. Time Spent Before the Mast: An Emerging Role for Mast Cells in Prosthetic Breast Implant Capsule Formation. Aesthetic Plastic Surgery. 2014 Jun 6. [Epub ahead of print]
- Rogers NM, Isenberg JS. Endothelial Cell Global Positioning System (GPS) for Pulmonary Arterial Hypertension - Homing in on Vascular Repair. Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1336-8. Doi: doi: 10.1161/ATVBAHA.114.303877. PMID: 24951651