Lubomir B. Smilenov, Ph.D.
Assistant Professor of Radiation Oncology
Center for Radiological Research
Center for Radiological Research
630 West 168th Street
Telephone: (212) 305-5661
Fax: (212) 305-3229
BA, Sofia University, Sofia, Bulgaria, 1982
PhD, Bulgarian Academy of Sciences, Sofia, Bulgaria, 1991
Project 1: Role of heterozygosity for DNA repair genes in radiation response and radiation sensitivity
Loss of function of DNA repair genes has been implicated in the development of many types of cancer, but for the vast majority of cases there is no link to specific germline mutations. In the last several years heterozygosity leading to haploinsufficiency for proteins involved in DNA repair pathways was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced. Since the effect of heterozygosity for one protein is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Atm, Rad9 and Brca1 on cell transformation, apoptosis and cataractogenesis. Our results show that cells heterozygous for both Atm and Rad9 or Atm and Brca1 are more resistant to apoptosis are more sensitive to transformation by radiation when compared with wild-type controls or those cells haploinsufficient for only one of these proteins. Radiation induced cataractogenesis also depends on the genotype and at least for Atm and Rad9 genes is enhanced by combined haploinsufficiency for both genes.
Project 2: Role of miRNAs in radiation response
miRNA has recently emerged as an important regulator of gene expression, possibly regulating as many as one-third of all human genes. Despite some progress, the characterization of miRNA-related mechanisms is still in its initial stage. Our current works shows that significant changes in miRNA expression occurs after irradiation of normal human cells. These differences assign important regulatory functions for miRNA expressed in irradiated cells. The main hypothesis of our study is that miRNA expression will very specifically reflect the type and dose of radiation, and that the combination of miRNA and gene expression profiling will characterize radiation responses even better. The integration of miRNA and gene expression analysis will definitely increase our understanding of the mechanisms involved in the cellular response to stress. The studies, which build from cell models to mouse models to whole human blood, represent a comprehensive set of experiments that will allow us to build on results from each stage. The integrated interpretation of these results is intended to accelerate our understanding of the signaling mechanisms involved in the response to ionizing radiation in general, and to protons and HZE particles specifically, and to facilitate discovery of new biomarkers for biodosimetry.
Project 3: The effect of high LET radiation on differentiation and tumorigenesis in the human hematopoietic system: modeling in vitro and in vivo for risk assessment
The goal of the study is to contribute to the high-LET carcinogenesis risk estimation by in vivo data acquired from human hematopoietic system reconstituted in immunodeficient mice. We expect the planned studies to show for first time 1) data on high LET radiation induced carcinogenesis in human hematopoietic system, 2) data on high-LET radiation induced in vivo chromosomal aberrations of human hematopoietic stem and progenitor cells and 3) in vivo data on the effects of high-LET radiation on human hematopoiesis.
S. Paul, L.B. Smilenov, and S.A. Amundson. Widespread decreased expression of immune function genes in human peripheral blood following radiation exposure. Radiat Res. 180:575-583 (2013).
T. Templin, E.F. Young, and L.B. Smilenov. Proton radiation induced miRNA signatures in mouse blood: characterization and comparison with (56)Fe -ion and gamma radiation. Int J Radiat Biol (2012).
Young EF, Smilenov LB. Impedance-based surveillance of transient permeability changes in coronary endothelial monolayers after exposure to ionizing radiation. Radiat Res 176, 415-424, 2011.
Wang J, Su F, Smilenov LB, Zhou L, Hu W, Ding N, Zhou G. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity. Radiat Oncol 6, 96, 2011.
Templin T, Paul S, Amundson SA, Young EF, Barker CA, Wolden SL, Smilenov LB. Radiation-induced micro-RNA expression changes in peripheral blood cells of radiotherapy patients. Int J Radiat Oncol Biol Phys 80, 549-557, 2011.
Templin T, Amundson SA, Brenner DJ, Smilenov LB. Whole mouse blood microRNA as biomarkers for exposure to γ-rays and (56)Fe ion. Int J Radiat Biol 87, 653-662, 2011.
Amundson SA, Smilenov LB. Integration of biological knowledge and gene expression data for biomarker selection: FN1 as a potential predictor of radiation resistance in head and neck cancer.Cancer Biol Ther 10, 1252-5, 2011.Zhou G, Smilenov LB, Lieberman HB, Ludwig T, Hall, EJ Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1. Adv Space Res 46, 681-686, 2010.
Su F, Smilenov LB, Ludwig T, Zhou L, Zhu J, Zhou G, Hall EJ. Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis. Radiat Oncol 5, 15, 2010.
Kleiman NJ, David J, Elliston CD, Hopkins KM, Smilenov LB, Brenner DJ, Worgul BV, Hall EJ, Lieberman HB. Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice. Radiat Res 168, 567-73, 2007.
Schwartz EI, Smilenov LB, Price MA, Osredkar T, Baker RA, Ghosh S, Shi FD, Vollmer TL, Lencinas A, Stearns DM, Gorospe M, Kruman II. Cell cycle activation in postmitotic neurons is essential for DNA repair. Cell Cycle 6, 318-29, 2007.
Xu A, Smilenov LB, He P, Masumura K, Nohmi T, Yu Z, Hei TK. New insight into intrachromosomal deletions induced by chrysotile in the gpt delta transgenic mutation assay. Environ Health Perspect 115, 87-92, 2007.
Hall EJ, Worgul BV, Smilenov L, Elliston CD, Brenner DJ. The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene. Radiat Environ Biophys 45, 99-104, 2006.