Oxidative stress, Neurogenesis, Stem cells, Transplantation, Chemobrain, Irradiation, Cognitive dysfunction
Stem cell research in my lab is focused on the mechanisms regulating stress responses in compromised tissue beds, and how stem cells can be used to lessen the severity of radiation- and chemotherapy-induced normal tissue injury in the brain. Current research has evolved from a formal training in radiation biology and from past studies investigating radiation-induced genomic instability and redox stress biology. Significant effort is focused on elucidating the molecular and biochemical mechanisms regulating the response of stem cells within the irradiated microenvironment.
Current research seeks to define the mechanisms underlying the beneficial effects of stem cell transplants on radiation-induced cognitive dysfunction. This work has also expanded to define the mechanisms underlying chemotherapy-induced cognitive decrements, as condition commonly referred to as “chemobrain.” Significant research is focused on determining how transplanted stem cells improve cognition after irradiation and chemotherapy, efforts designed to ameliorate the adverse cognitive side effects suffered in millions of cancer survivors subjected to various irradiation and chemotherapeutic regimes. Correspondingly, significant work in my lab is now focused on stem cell strategies as potentially useful and novel clinical interventions for improving long-term cognitive health following cytotoxic cancer treatments.
Long standing interests continues to explore the adverse effects of exposure to the space radiation environment, where in vitro and in vivo models are used to define biological responses to charged particle irradiation. These efforts have defined the importance of radiation-induced oxidative stress as a biochemical mechanism regulating the functionality of neural stem cells. Much of this work is also applied to the field of low dose radiobiology, where the impact of environmentally relevant exposures to the CNS of sparsely ionizing radiation are evaluated. Projects focused on understanding radiation effects of charged particles in space or low dose terrestrial exposures are aimed at defining specific risks to human health, such as carcinogenesis,neurodegeneration,cognitive performance.
Selected Publications since 2000:
Limoli, C.L., Giedzinski, E., Morgan, W.F. and Cleaver, J.E. Polymerase ? deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair. Proc. Natl. Acad. Sci. USA 97:7939-7946 (2000).
Limoli, C.L., Ponnaiya, B., Corcoran, J.J., Giedzinski, E. and Morgan, W.F. Chromosomal instability induced by heavy ion irradiation. Int. J. Radiat. Biol. 76:1599-1606 (2000).
Limoli, C.L., Corcoran, J.J., Jordan, R., Morgan, W.F. and Schwartz, J. A role for chromosomal instability in the development of and selection for radioresistant cell variants. Br. J. Cancer 84:489-492 (2001).
Limoli, C.L., Kaplan, M.I., Giedzinski, E. and Morgan, W.F. Attenuation of radiation-induced genomic instability by free radical scavengers and cellular proliferation. Free Radic. Biol. Med. 31:10-19 (2001).
Limoli, C.L., Giedzinski, E., Bonner, W.M. and Cleaver, J.E. UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, ?-H2AX formation, and Mre11 relocalization. Proc. Natl. Acad. Sci. USA, 99:233-238 (2002).
Cleaver, J.E., Bartholomew, J., Char, D., Crowley, E., Feeney, L. and Limoli, C.L. Polymerase ? and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation. DNA Repair 1:41-57 (2002).
Morgan, W.F., Hartmann, A., Limoli, C.L., Nagar, S. and Ponnaiya, B. Bystander effects in radiation-induced genomic instability. Mutat. Res. 504:91-100 (2002).
Limoli, C.L., Laposa, R. and Cleaver, J.E. DNA replication arrest in XP Variant cells after UV exposure is diverted into an Mre11-dependent recombination pathway by the kinase inhibitor wortmannin. Mutat. Res. 510:121-129 (2002).
Thompson, L.H. and Limoli, C.L. Origin, recognition, signaling and repair of DNA double-strand breaks in mammalian cells. In: Eukaryotic Signaling and Repair (Ed. K. Caldecott), Landes Biosciences, Georgetown, TX, Chapter 7, pp. 1-39 (2003).
Limoli, C.L., Giedzinski, E., Morgan, W.F., Swarts, S.G., Jones, G.D.D. and Hyun, W. Persistent oxidative stress in chromosomally unstable cells. Cancer Res. 63:3107-3111 (2003).
Cleaver, J.E., Laposa, R.R. and Limoli, C.L. DNA replication in the face of (in)surmountable odds. Cell Cycle, 2:310-315 (2003).
Limoli, C.L. and Giedzinski, E. Induction of chromosomal instability by chronic oxidative stress. Neoplasia, 5:339-346 (2003).
Limoli, C.L., Giedzinski, E, Radoslaw Rola, Shinji Otsuka, Palmer, T.D. and Fike, J.R. Radiation response of neural precursor cells: linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress. Radiat. Res. 161:17-27 (2004).
Rola, R., Otsuka, S., Obenaus, A., Nelson, G.A., Limoli, C.L., Vandenberg, S.R. and Fike, J.R. Indicators of hippocampal neurogenesis are altered by 56Fe irradiation in a dose dependent manner. Radiat. Res. 162:442-446 (2004).
Limoli, C.L., Rola, R., Giedzinski, E., Mantha, S., Huang, T-T. and Fike, J.R. Cell-density-dependent regulation of neural precursor cell function. Proc Natl Acad Sci USA 101:16052-116057 (2004).
Limoli, C.L., Giedzinski, E. and Cleaver, J.E. Alternative recombination pathways in UV-irradiated XP Variant cells. Oncogene 24:3708-3714 (2005).
Rola, R., Sarkissian, V., Obenaus, A., Nelson, G.A., Otsuka, S., Limoli, C.L. and Fike, J.R. High LET irradiation induced inflammation and persistent changes in markers of hippocampal neurogenesis. Radiat. Res. 164:556-560 (2005).
Giedzinski, E., Rola, R., Fike, J. and Limoli, C.L. Efficient production of reactive oxygen species in neural precursor cells following exposure to 250 MeV Protons. Radiat. Res. 164:540-544 (2005).
Limoli, C.L., Giedzinski, E., Baure, J., Rola, R., and Fike, J.R. Altered growth and radiosensitivity in neural precursor cells subjected to oxidative stress. Int. J. Radiat. Biol. 82: 640-647 (2006).
Limoli, C.L., Giedzinski, E., Baure, J., Doctrow, S.R., Rola, R., and Fike, J.R. Using superoxide dismutase/catalase mimetics to manipulate the redox environment of neural precursor cells. Radiat. Protect. Dosimetry, 122:228-236 (2006).
Fike, J.R., Rola, R.R., and Limoli, C.L. Radiation response of neural precursor cells. Neurosurg. Clin. N. Amer. 18:115-127, 2007.
Rola, R., Zou, Y., Huang, T-T., Fishman, K., Baure, J., Rosi, S., Milliken, H., Limoli, C.L. and Fike J.R. Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radical Biology & Medicine. 42:1133-1145 (2007).
Limoli, C.L., Giedzinski, E., Baure, J., Rola, R., and Fike J.R. Redox changes induced in hippocampal precursor cells by heavy ion irradiation. Radiat. Environ. Biophys., 46:167-172 (2007).
Feraudy, S., Limoli, C.L., Giedzinski, E., Karentz, D., Marti, T., Feeney, L. and Cleaver J.E. Pol h is required for DNA replication during nucleotide deprivation by hydroxyurea. Oncogene 26:5713-5721 (2007).
Dayal, D., Martin, S.M., Limoli, C.L. and Spitz D.R. Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells. Biochem J. 413:185-191 (2008).
Kondo, H., Searby, N.D., Mojarrab, R., Phillips, J., Alwood, J., Yumoto, K., Almeida, E.A.C., Limoli, C.L. Globus, R.K. Total body irradiation of post-pubertal mice with 137-Cesium acutely compromises the microarchitecture of cancellous bone and increases osteoclasts. Radiat. Res. 171:283-289 (2009).
Baure, J., Izadi, A., Suarez, V., Giedzinski, E., Cleaver, J.E., Fike, J.R. and Limoli, C.L. Histone H2AX phosphorylation in response to changes in chromatin structure induced by altered osmolarity. Mutagenesis 24:161-167 (2009).
Fike, J., Rosi, S. and Limoli, C.L. Neural precursor cells and central nervous system radiation sensitivity. Sem. Radiat. Onc. 19:122-132 (2009).
Dayal, D., Martin, S.M., Owens, K.M., Boominathan, A., Pain, D., Limoli, C.L., Goswami, P.H., Domann, F.E. and Spitz, D.R. Mitochondrial complex II dysfunction can significantly contribute to genomic instability following ionizing radiation. Radiat. Res. 172:737-745 (2009).
Fishman, K., Baure, J., Zou, Y., Huang, T-T., Andres-Mach, M., Rola, R., Suarez, T., Acharya, M., Limoli, C.L., Lamborn, K.R., Fike, J.R. Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in CuZnSOD or MnSOD. Free Radical Biology & Medicine. 47:1459-1467 (2009).
Acharya, M., Christie, L.-A., Lan, M., Donovan, P.J., Cotman, C.W., Fike, J.R. and Limoli, C.L. Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc. Natl. Acad. Sci. USA 106:19150-19155 (2009).
Kondo, H., Yumoto, K., Alwood, J., Mojarrab, R., Wang, A., Almeida, E. A. C., Searby, N. D., Limoli, C. L. and Globus, R. K. Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse. J. App. Physiology 108:152-161 (2010).
Yumoto, K., Globus, R. K., Mojarrab, R., Arakaki, J., Wang, A., Searby, N. D., Almeida, E. A. C. and Limoli, C. L. Short-term effects of whole body exposure to 56Fe ions in combination with musculoskeletal disuse on bone cells. Radiat. Res. 173:494-504 (2010).
Caiozzo, V.J., Giedzinski, E., Baker, M., Suarez, T., Izadi, A., Lan, M.L., Cho-Lim, J., Tseng, B.P. and Limoli, C.L. The radiosensitivity of satellite cells: Cell cycle regulation, apoptosis, and oxidative stress. Radiat. Res. 174: 582-589 (2010).
Alwood, J.S., Yumoto, K., Mojarrab, R., Limoli, C.L., Almeida, E.A.C., Searby, N.D. and Globus, R.K. Heavy ion irradiation and unloading effects on mouse lumbar vertebral microarchitecture, mechanical properties and tissue stresses. Bone, 47:248-255 (2010).
Acharya, M., Lan, M., Kan, V., Patel, N., Giedzinski, E., Tseng, B.P. and Limoli, C.L. Consequences of ionizing radiation-induced damage in human neural stem cells. Free Radic. Biol. Med. 49:1846-1855 (2010).
Cho-Lim, J.J., Caiozzo, V.J., Tseng, B.P., Giedzinski, E., Baker, M and Limoli, C.L. Satellite cells say NO to radiation. Radiat. Res. 175:561-568 (2011).
Krasieva, T.B., Giedzinski, E., Tran, K., Lan, M.L., Limoli, C.L. and Tromberg, B.J. Probing the impact of gamma-irradiation on the metabolic state of neural stem and precursor cells using dual-wavelength intrinsic signal two-photon excited fluorescence. J. Innov. Optical Health Sci. 4:289-300 (2011).
Acharya, M., Christie, L.-A., Lan, M., Giedzinski, E., Fike, J.R., Rosi, S. and Limoli, C.L. Human neural stem cell transplantation ameliorates radiation-induced cognitive dysfunction. Cancer Res. 71:4834-4845 (2011).