Joel S. Greenberger, MD, FACRO, FACR

  • Professor and Chairman, Radiation Oncology

I am currently the principal investigator on the Center for Medical Countermeasures Against Radiation (CMCR) Grant from the NIAID. I am also principal investigator on Project 1 “MnSOD-PL Intravenous Administration for Prevention of Total Body Irradiation-Induced Toxicity” and the principal investigator on the Pilot Projects Core and the Education and Development Core of the CMCR Grant. The CMCR Program, with its four projects and six cores, seeks to optimize MnSOD-PL gene therapy for systemic radiation protection (agents delivered after radiation exposure) to protect first responders entering a blast area for a dirty bomb or fission bomb terrorist attack. The projects in the CMCR are also focused on developing new small molecule radiation mitigators (agents delivered after radiation exposure) to decrease the toxicity of radiation and stimulate survival of individuals who would normally be victims of bone marrow or intestinal radiation injury. Project 1 seeks to determine the potentially deleterious late effects of total body radiation protection in surviving mice that are protected from otherwise lethal total body irradiation. Male, female, and pregnant female mice are being followed for their lifespan, and litters born to pregnant females who have survived irradiation by small molecule therapy are being followed for teratogenic effects of this radiation protection.

Teaching Activities

Invited lecturer: RITN, Fanconi Anemia Research Society, CMCR Annual Meeting, Medical students and residents, Department of Radiation Oncology, UPCI

Representative Publications

Sharlow ER, Leimgruber S, Lira A, McConnell MJ, Norambuena A, Bloom GS, Epperly MW, Greenberger JS, Lazo JS. A Small Molecule Screen Exposes mTOR Signaling Pathway Involvement in Radiation-Induced Apoptosis. ACS Chem Biol. 2016 May 20;11(5):1428-37. doi: 10.1021/acschembio.5b00909. Epub 2016 Mar 14. PubMed PMID: 26938669.

Huang Z, Epperly M, Watkins SC, Greenberger JS, Kagan VE, Bayır H. Necrostatin-1 rescues mice from lethal irradiation. Biochim Biophys Acta. 2016 Apr;1862(4):850-6. doi: 10.1016/j.bbadis.2016.01.014. Epub 2016 Jan 20. PubMed PMID: 26802452; PubMed Central PMCID: PMC4788560.

Shinde A, Berhane H, Rhieu BH, Kalash R, Xu K, Goff J, Epperly MW, Franicola D, Zhang X, Dixon T, Shields D, Wang H, Wipf P, Parmar K, Guinan E, Kagan V, Tyurin V, Ferris RL, Zhang X, Li S, Greenberger JS. Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2(-/-) (C57BL/6) Mice. Radiat Res. 2016 Feb;185(2):134-50. doi: 10.1667/RR14035.1. Epub 2016 Jan 20. PubMed PMID: 26789701; PubMed Central PMCID: PMC4773657.

Zhang H, Kozono DE, O’Connor KW, Vidal-Cardenas S, Rousseau A, Hamilton A, Moreau L, Gaudiano EF, Greenberger J, Bagby G, Soulier J, Grompe M, Parmar K, and D’Andrea AD.  TGF-β inhibition rescues hematopoietic stem cell defects and bone marrow failure in Fanconi Anemia.  Cell Stem Cell, 18: 1-14, 2016.

Gomez-Casal R, Epperly MW, Wang H, Proia DA, Greenberger JS, Levina V. Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition. Oncotarget. 2015 Dec 29;6(42):44306-22. doi: 10.18632/oncotarget.6248. PubMed PMID: 26517240; PubMed Central PMCID: PMC4792558.

Dickson R, Kim JO, Huq MS, Bednarz G, Suyama J, Yealy DM, Wang H, Greenberger  JS. A Mobile Alert System for Preparing the Delivery of Radiation Mitigators. In Vivo. 2015 Sep-Oct;29(5):505-13. PubMed PMID: 26359406.

Wang X, Wei L, Cramer JM, Leibowitz BJ, Judge C, Epperly M, Greenberger J, Wang F, Li L, Martin MG, Lagasse E, Zhang L, Yu J.  Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation. Scientific Reports, 5:8566, 2015.

Greenberger J, Kagan V, Bayir H, Wipf P, and Epperly M.  Antioxidant approaches to management of ionizing irradiation injury.  Antioxidants, 4:82-101, 2015.

Kabolizadeh P, Kalash R, Huq MS, Greenberger JS, Heron DE, Beriwal S. Dosimetric definitions of total lung volumes in calculating parameters predictive for radiation-induced pneumonitis. Am J Clin Oncol. 2015 Aug;38(4):401-4. doi: 10.1097/COC.0b013e3182a2588f. PubMed PMID: 24064747.

Brenner DJ, Chao NJ, Greenberger JS, Guha C, McBride WH, Swartz HM, Williams JP. Are We Ready for a Radiological Terrorist Attack Yet? Report From the Centers for Medical Countermeasures Against Radiation Network. Int J Radiat Oncol Biol Phys. 2015 Jul 1;92(3):504-5. doi: 10.1016/j.ijrobp.2015.02.042. PubMed PMID: 26068482; PubMed Central PMCID: PMC4467463.

Gill BS, Beriwal S, Rajagopalan MS, Wang H, Hodges K, Greenberger JS. Quantitative evaluation of radiation oncologists' adaptability to lower reimbursing treatment programs. Pract Radiat Oncol. 2015 Jul-Aug;5(4):267-73. doi: 10.1016/j.prro.2014.10.014. Epub 2014 Nov 5. PubMed PMID: 25544552.

Gomez-Casal R, Bhattacharya C, Epperly MW, Basse PH, Wang H, Wang X, Proia DA, Greenberger JS, Socinski MA, Levina V. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells. Cancers (Basel). 2015 May 22;7(2):876-907. doi: 10.3390/cancers7020814. PubMed PMID: 26010604; PubMed Central PMCID: PMC4491689.

Rhieu BH, Shinde A, Epperly MW, Dixon T, Wang H, Chaillet R, Greenberger JS. Organ-specific responses of total body irradiated doxycycline-inducible manganese superoxide dismutase Tet/Tet mice. In Vivo. 2014 Nov-Dec;28(6):1033-43. PubMed PMID: 25398796.

Shinde A, Epperly MW, Cao S, Holt D, Goff J, Shields D, Franicola D, Wipf P,  Wang H, Greenberger JS. Improved hematopoiesis in GS-nitroxide (JP4-039)-treated  mouse long-term bone marrow cultures and radioresistance of derived bone marrow stromal cell lines. In Vivo. 2014 Sep-Oct;28(5):699-708. PubMed PMID: 25189880.

Liu B, Bhatt D, Oltvai ZN, Greenberger JS, Bahar I. Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies. Sci Rep. 2014 Sep 1;4:6245. doi: 10.1038/srep06245. PubMed PMID: 25175563; PubMed Central PMCID: PMC4150106.

Shinde A, Epperly MW, Cao S, Franicola D, Shields D, Wang H, Wipf P, Sprachman MM, Greenberger JS. Effects of the bifunctional sulfoxide MMS350, a radiation mitigator, on hematopoiesis in long-term bone marrow cultures and on radioresistance of marrow stromal cell lines. In Vivo. 2014 Jul-Aug;28(4):457-65. PubMed PMID: 24982210.

Rhieu BH, Epperly MW, Cao S, Franicola D, Shields D, Goff J, Wang H, Greenberger JS. Increased hematopoiesis in long-term bone marrow cultures and reduced irradiation-induced pulmonary fibrosis in Von Willebrand factor homologous deletion recombinant mice. In Vivo. 2014 Jul-Aug;28(4):449-56. PubMed  PMID: 24982209.

Rhieu BH, Epperly MW, Cao S, Goff J, Shields D, Franicola D, Wang H, Greenberger JS. Improved longevity of hematopoiesis in long-term bone marrow cultures and reduced irradiation-induced pulmonary fibrosis in Toll-like receptor-4 deletion recombinant-negative mice. In Vivo. 2014 Jul-Aug;28(4):441-8. PubMed PMID: 24982208.

Epperly MW, Goff JP, Franicola D, Wang H, Wipf P, Li S, Greenberger JS. Esophageal radioprotection by swallowed JP4-039/F15 in thoracic-irradiated mice with transgenic lung tumors. In Vivo. 2014 Jul-Aug;28(4):435-40. PubMed PMID: 24982207.

Berhane H, Shinde A, Kalash R, Xu K, Epperly MW, Goff J, Franicola D, Zhang X, Dixon T, Shields D, Wang H, Wipf P, Li S, Gao X, Greenberger JS. Amelioration of radiation-induced oral cavity mucositis and distant bone marrow suppression in fanconi anemia Fancd2-/- (FVB/N) mice by intraoral GS-nitroxide JP4-039. Radiat Res. 2014 Jul;182(1):35-49. doi: 10.1667/RR13633.1. Epub 2014 Jun 16. PubMed PMID: 24932534; PubMed Central PMCID: PMC4101533.

Tyurina YY, Poloyac SM, Tyurin VA, Kapralov AA, Jiang J, Anthonymuthu TS, Kapralova VI, Vikulina AS, Jung MY, Epperly MW, Mohammadyani D, Klein-Seetharaman J, Jackson TC, Kochanek PM, Pitt BR, Greenberger JS, Vladimirov YA, Bayır H, Kagan VE. A mitochondrial pathway for biosynthesis of lipid mediators. Nat Chem. 2014 Jun;6(6):542-52. doi: 10.1038/nchem.1924. Epub 2014 Apr 20. PubMed PMID: 24848241; PubMed Central PMCID: PMC4201180.

Kalash R, Berhane H, Au J, Rhieu BH, Epperly MW, Goff J, Dixon T, Wang H, Zhang X, Franicola D, Shinde A, Greenberger JS. Differences in irradiated lung gene transcription between fibrosis-prone C57BL/6NHsd and fibrosis-resistant C3H/HeNHsd mice. In Vivo. 2014 Mar-Apr;28(2):147-71. PubMed PMID: 24632969; PubMed Central PMCID: PMC4074886.

Kanter DJ, O'Brien MB, Shi XH, Chu T, Mishima T, Beriwal S, Epperly MW, Wipf  P, Greenberger JS, Sadovsky Y. The impact of ionizing radiation on placental trophoblasts. Placenta. 2014 Feb;35(2):85-91. doi:10.1016/j.placenta.2013.12.011. Epub 2014 Jan 2. PubMed PMID: 24418702; PubMed Central PMCID: PMC3954710.

Greenberger JS, Berhane H, Shinde A, Rhieu BH, Bernard M, Wipf P, Skoda EM, Epperly MW. Can Radiosensitivity Associated with Defects in DNA Repair be Overcome by Mitochondrial-Targeted Antioxidant Radioprotectors. Front Oncol. 2014 Feb 17;4:24. doi: 10.3389/fonc.2014.00024. eCollection 2014. PubMed PMID: 24596683; PubMed Central PMCID: PMC3926189.

Kalash R, Berhane H, Yang Y, Epperly MW, Wang H, Dixon T, Rhieu B, Greenberger JS, Huq MS. Improved survival of mice after total body irradiation with 10 MV photon, 2400 MU/min SRS beam. In Vivo. 2014 Jan-Feb;28(1):1-12. PubMed PMID: 24425830; PubMed Central PMCID: PMC4046118.

Berhane H, Epperly MW, Goff J, Kalash R, Cao S, Franicola D, Zhang X, Shields D, Houghton F, Wang H, Wipf P, Parmar K, Greenberger JS. Radiologic differences between bone marrow stromal and hematopoietic progenitor cell lines from Fanconi  Anemia (Fancd2(-/-)) mice. Radiat Res. 2014 Jan;181(1):76-89. doi:10.1667/RR13405.1. Epub 2014 Jan 7. PubMed PMID: 24397476; PubMed Central PMCID:  PMC3970166.

Research Interests

Dr. Greenberger is currently Principal Investigator on the Center for Medical Countermeasures Against Radiation (CMCR) Grant from the NIAID.  He also is Principal Investigator on Project 1 “MnSOD-PL Intravenous Administration for Prevention of Total Body Irradiation-Induced Toxicity,” and the Principal Investigator on the Pilot Projects Core, and the Education and Development Core of the CMCR Grant.  The CMCR Program, with its four projects and six cores, seeks to optimize MnSOD-PL gene therapy for systemic radiation protection (agents delivered after radiation exposure) to protect first responders entering a blast area for a dirty bomb or fission bomb terrorist attack.  The projects in the CMCR are also focused on developing new small molecule radiation mitigators (agents delivered after radiation exposure) to decrease the toxicity of radiation and stimulate survival of individuals who would normally be victims of bone marrow or intestinal radiation injury.  Project 1 seeks to determine the potentially deleterious late effects of total body radiation protection in surviving mice that are protected from otherwise lethal total body irradiation.  Male, female, and pregnant female mice are being followed for their lifespan, and litters born to pregnant females who have survived irradiation by small molecule therapy are being followed for teratogenic effects of this radiation protection.

Projects 2, 3, and 4 (Drs. Valerian Kagan, Jian Yu, and Hulya Bayir) seek to develop small molecule mitochondrially targeted drugs for radiation protection and mitigation.

“Prevention of Pulmonary Fibrosis by MnSOD-PL Gene Therapy”:  This grant, currently in its eighth year, seeks to develop methods by which to deliver inhaled MnSOD-PL to the lung of mice, using a nebulizer system, and then to translate this into the clinic for inhalation gene therapy protection of the lung during high dose chemoradiotherapy of lung cancer.  A significant late toxicity of pulmonary irradiation is pulmonary fibrosis. This laboratory has proven that the origin of cells producing the fibrotic lesion of the lung is from mesenchymal stem cells (bone marrow stromal cells) derived from the bone marrow.  Methods by which to decrease bone marrow stromal cell migration into the lungs have included demonstration that the SMAD3-/- bone marrow chimeric mice show decreased fibroblast migration in the lungs, due to their inability to respond to TGFβ, the cytotoxic cytokine and fibrosis inducing cytokines produced by irradiated lung.  Our laboratory has also demonstrated the bone marrow origin of fibroblast progenitor cells for the fibrotic lesions in pulmonary fibrosis. Research is currently underway to determine the initial molecular events in irradiated lung which lead to TGFβ production and initiation of migration of bone marrow cells forming fibrosis.

Dr. Greenberger is Co-Investigator on one R01 grant entitled “Rational Design of Lipidic Vectors for Mitochondria-Targeted Antioxidants (NIGM)”.

Research Grants

Faculty Support on Research grants is 46 percent.

U19 AI0680201-11 (Greenberger)                   09/01/15 – 08/31/20                1.00 calendar month

NIH/NIAID                                                      $2,381,415 DC ($1,285,964 IDC)

Mechanism-Directed Sequential Delivery of Radiation Mitigators

Core A, Administrative Core

The Administrative Core coordinates four projects, six scientific core entities, and the University of Pittsburgh CMCR with the other three CMCR Programs (Duke, Columbia, and UCLA).

Role: Principal Investigator

U19 AI0680201-11 (Greenberger)                   09/01/15 – 08/31/20                1.00 calendar month

NIH/NIAID                                                      $2,381,415 DC ($1,285,964 IDC)

Mechanism-Directed Sequential Delivery of Radiation Mitigators

Core C, Radiobiological Standardization Core

Enter Description

Role: Core Co-Investigator

U19 AI0680201-11 (Greenberger)                   09/01/15 – 08/31/20                3.60 calendar month

NIH/NIAID                                                      $2,381,415 DC ($1,285,964 IDC)

Mechanism-Directed Sequential Delivery of Radiation Mitigators

Project 1: Sequenced Directed Delivery of Radiation Mitigators

Project 1 in the CMCR is focused on using plasma cytokine protein signatures to determine the optimal time for delivery of a second radiation mitigator after GS-nitroxide has been delivered at 24 hrs. after total body irradiation.

Role: Project Co-Investigator

U19 AI0680201-11 (Greenberger)                   09/01/15 – 08/31/20                1.20 calendar month

NIH/NIAID                                                      $2,381,415 DC ($1,285,964 IDC)

Mechanism-Directed Sequential Delivery of Radiation Mitigators

CMCR Coordinating Center Core

The goal of this core is to prepare web-based sites for access of archived data from the four CMCR programs, to design a radiation biology and methods website for education of scientists at all levels, to coordinate yearly meetings, and to provide steering committee telephone conference calls monthly.

Role: Core Leader

R01 GM102989 (Li)                                        05/01/13 – 04/30/17                0.24 calendar months  

NIH                                                                 $4,577 DC ($2472 IDC)

Rational Design of Lipidic Vectors for Mitochondria-Targeted Antioxidants (NIGM) 0.24 calendar months

This research is designed to produce lipidic (liposomal) vehicles for delivering water-insoluble radiation mitigators.

Role: Co-Investigator