Dr. Greenberger’s research focuses on the development of small molecule radiation protectors (delivered before irradiation exposure) and mitigators (delivered after irradiation exposure, but before the onset of symptoms and signs of radiation damage). This research has been funded by the National Institutes of Allergies and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) now for 13 years. Dr. Greenberger is the Principal Investigator on the University of Pittsburgh Center for Medical Countermeasures Against Radiation (CMCR), one of four such centers in the United States. He oversees four projects dealing with the concept of “radiation disease”, which describes categories of organ systems failure related to the time after total body irradiation exposure. His research efforts focus on multiple forms of irradiation-induced cell death including: apoptosis, necroptosis, ferroptosis, and secondary injury mediated by release of inflammatory cytokines from irradiated tissues. Research in the CMCR Program involves University of Pittsburgh faculty from the departments of Pathology, Critical Care Medicine, Chemistry, Biostatistics, Computational Biology, and the University of Pittsburgh School of Public Health, Environmental Sciences Department. Research has led to the discovery of multiple new categories of radiation mitigators including the GS-nitroxides (lead compound, JP4-039), necrostatin, and identified pathways of irradiation-induced damage to the bone marrow and intestine based on delineation of the sequence of events from the molecular to intercellular, intracellular, and distant abscopal effects mediated by inflammatory cytokines and cell breakdown products released from irradiated tissue. Translation of drug discovery from the CMCR into clinical application has led to preclinical models of the use of JP4-039 to ameliorate irradiation toxicity to the oral cavity and oropharynx, applicable to Head and Neck Cancer patients, and to the esophagus, applicable to Esophagus and Lung Cancer patients to minimize normal tissue damage and decrease radiation side effects. In addition, Dr. Greenberger has active research programs in biology of adipocyte stem cells, animal models of Amyotrophic Lateral Sclerosis (ALS), and has focused research on combined injury (radiation plus trauma, radiation plus infection, radiation plus thermal burn, and radiation plus bone fracture). Activities are available for medical students wishing to spend a year in basic science research, graduate students, and post-doctoral fellows seeking to gain expertise and learn Radiation Biology.
Teaching Activities
Invited lecturer: RITN, Fanconi Anemia Research Society, CMCR Annual Meeting, Medical students and residents, Department of Radiation Oncology, UPCI
Representative Publications
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.
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.
Glowacki J. Mizuno S, Kung J, Goff J, Epperly M, Dixon T, Wang H, and Greenberger JS. Effects of mouse genotype on bone wound healing and irradiation-induced delay. In Vivo. 2014 28: 189-196. PMID: 24632972
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
Leibowitz BJ, Wei L, Zhang L, Ping X, Epperly M, Greenberger J, Cheng T, and Yu J. Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice. Nature Communications 2014 Mar 18;5:3494. PMID: 24637717
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
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.
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. PMID: 25189880
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, 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
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.
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.
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.
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
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. PubMed PMID: 25544552.
Greenberger J, Kagan V, Bayir H, Wipf P, and Epperly M. Antioxidant approaches to management of ionizing irradiation injury. Antioxidants, 4:82-101, 2015.
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.
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.
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.
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.
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
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.
Stoyanovsky DA, Jiang J, Murphy MP, Epperly M, Zhang X, Li S, Greenberger J, Kagan V, Bayır H. Design and synthesis of a mitochondria-targeted mimic of glutathione peroxidase, MitoEbselen-2, as a Radiation Mitigator. ACS Med Chem Lett, 2016 June1:7(6): 653-4. doi: 10.1021/acsmedchemlett.6b00212. PMID: 27326344
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.
Song X, Xie Y, Kang R, Hou W, Sun X, Epperly M, Greenberger JS, and Tang D. FANCD2 protects against bone marrow injury from ferroptosis. Biochemical and Biophysical Communications, 2016 Nov 18; 480(3): 443-449. PMID: 277773819
Wei L, Leibowitz BJ, Wang X, Epperly M, Greenberger J, Zhang L, and Yu J. Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice. Journal of Clinical Investigation, 2016 Nov 1;126(11): 4076-4086. PMID: 27701148
Zhang X, Hou W, Epperly MW, Rigatti L, Wang H, Franicola D, Sivanathan A, Greenberger JS. Evolution of malignant plasmacytoma cell lines from K14E7 Fancd2-/- mouse long-term bone marrow cultures. Oncotarget, 2016. Oct 18; 7(42): 68449-68472. Doi: 10. 18632/oncotarget.12036. PMID: 27637088. PMCID: PMC5356567
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.
Kagan VE, Mao G, Qu F, Angeli JPF, Doll S, St. Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, Kapralov AA, Amoscato AA, Jiang J, Anthonymuthu T, Mohammadyani D, Yang Q, Poneth B, Klein-Seetharaman J, Watkins S, Bahar I, Greenberger J, Mallampalli RP, Stockwell BR, Tyurina YY, Conrad M, and Bayir H. Oxidized arachidonic and adrenic Pes navigate cells to ferroptosis. Nature Chemical Biology 2017 Jan 13(1): 81-90 doi 10.1038/nchembio.2238. PMID: 27842066. PMCID: PMC5506843
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
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
Brand RM, Epperly MW, Stottlemyer JM, Skoda EM, Gao X, Li S, Huq S, Wipf P, Kagan VE, Greenberger JS, and Falo, LD Jr. A topical mitochondria-targeted redox cycling nitroxide mitigates oxidative stress induced skin damage. Journal Investgative Dermatology. 2017 Mar; 137(3): 576-586. Doi: 10.1016/j.jid.2016.09.033. PMID: 27794421. PMCID: PMC5466072
Epperly MW, Sacher JR, Krainz T, Zhang X, Wipf P, Liang M, Fisher R, Li S, Wang H, Greenberger JS. Effectiveness of analogues of the GS-nitroxide, JP4-039, as total body radiation mitigators. In Vivo 2017. Jan2; 31: 39-44. PMID: 28064218 PMCID: PMC5267945.
Epperly MW, Rhieu BH, Franicola D, Dixon T, Cao S, Zhang X, Shields D, Wang H, Wipf P, Greenberger JS. Induction of TGF-β by irradiation or chemotherapy in Fanconi Anemia (FA) mouse marrow is modulated by small molecule radiation mitigators JP4-039 and MMS350. In Vivo. 2017 Mar-Apr; 31: 159-168. PMID 28358695
Bernard ME, Glaser, SM, Gill BS, Beriwal S, Heron DE, Luketich JD, Friedland DM, Socinski MA, Greenberger JS. Results of a single institution experience with dose-escalated chemoradiation for locally advanced unresectable non-small cell lung cancer. Frontiers in Radiation Oncology 2017 Jan 23; 7:1. Doi:10.3389/fonc.2017.00001 PMID: 28168163
Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy B, Anker C, Thakrar H, Horiba N, Dubey A, Greenberger JS, Raben A, Giguere J, Roof K, Videtic G, Pollock J, Safran H, and Crane CH. Effect of the addition of Cetuximab to Paclitaxel, Cisplatin, and radiation therapy for patients with esophageal cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial, JAMA Oncology, 2017; doi: 10.1001/jamaoncol.2017.1598. PMID: 28687830. PMCID: PMC5710193
Epperly MW, Zhang X, Fisher R, Franicola D, Shields D, Quickel M, Hankey-Giblin P, Wang H, Greenberger JS. Reduced competitive repopulation capacity of totipotential hematopoietic stem cells in the bone marrow for Friend Virus infected Fv-2-resistant mice. In Vivo. 2017 May-Jun; 31(3): 313-320. PMID: 28438857. PMCID: PMC5461439
Glaser SM, Kalash R, Bongiorni DR, Roberts MS, Balasubramani GK, Jacobs BL, Beriwal S, Heron DE, Greenberger JS. Challenges in the analysis of outcomes for surgical compared to radiotherapy treatment of prostate cancer. In Vivo. 2018 Jan-Feb; 32(1): 113-120. PMID: 29275307
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 “Signature Directed Administration of Multiple Radiation Mitigators”, and the Principal Investigator on the Consortium Coordination Core of the four centers including (UCLA, Duke, and Columbia) in the CMCR Program. The CMCR Program, with its four projects and six cores, seeks to optimize drug discovery for delivery after radiation exposure to protect victims and 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 early and 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, Hulya Bayir, and Jian Yu) seek to develop small molecule mitochondrially targeted drugs for radiation protection and mitigation.
“Prevention of Irradiation Late Effects”: A NASA grant application currently in process seeks to develop methods by which to deliver diet and radiation mitigators to total body low dose rate irradiated mice. A significant late toxicity of pulmonary irradiation is pulmonary fibrosis. The 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 TGF-β, 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 lesion in pulmonary fibrosis. Research is currently underway to determine the initial molecular events in irradiated lung, which lead to TGF-β production and initiation of migration of bone marrow cells forming fibrosis.
Dr. Greenberger is also 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