Biological effects of radiation, with emphasis on carcinogenesis, cancer prevention and acute radiation effects.
Key words: Cancer, proteases, protease inhibitors, cancer prevention, oncogenes, gene expression, radiation acute effects, space radiation.
DESCRIPTION OF RESEARCH
Much of the current work of the Kennedy laboratory is focused on studies related to the acute radiation risks for astronauts exposed to solar particle event (SPE) radiation. SPEs can involve relatively high doses of radiation that can cause symptoms of the acute radiation syndrome (ARS), which may be exacerbated when combined with other space flight stressors, such that the mission or crew health may be compromised. The National Space Biomedical Research Institute (NSBRI) has established a Center of Acute Radiation Research (CARR), based at the University of Pennsylvania, to determine whether there are adverse acute biological effects like those of the ARS, which are likely to occur in astronauts exposed to the types of radiation, at the appropriate energies, doses and dose-rates, present during an SPE. The ARS is a phased syndrome which often includes vomiting and fatigue. Other acute adverse biologic effects of concern are the loss of hematopoietic cells, which can result in compromised bone marrow and immune cell functions. There is also concern for skin damage from high SPE radiation doses, including burns, and resulting immune system dysfunction. Using 3 separate animal model systems (ferrets, mice and pigs), the major biologic endpoints associated with the ARS being evaluated are: 1) vomiting/retching and fatigue, 2) hematologic and immune system changes, resulting from SPE radiation with and without reduced weightbearing conditions (which simulate hypogravity in animal model systems), and 3) skin injury and related immune system functions. In several areas of CARR research, statistically significant adverse health effects have been observed in animals exposed to SPE-like radiation(s). Studies in these areas of research include mechanistic studies on the radiation induced adverse effects and their mitigation or prevention by potential countermeasures. Some examples of study areas utilizing the CARR model systems include SPE radiation effects on: 1) lymphocyte and neutrophil activation and function in the presence and absence of countermeasures, 2) blood coagulation parameters, including disseminated intravascular coagulation, and 3) increased intracranial pressure and other consequences arising from exposure to space radiation.
Research in the Kennedy laboratory focused on cancer involves studies on the mechanism(s) involved in the induction of malignant transformation and its modification by various chemical agents. The modifying agents are cancer chemopreventive agents, with emphasis on protease inhibitors and agents known to modify free radical reactions. Studies on the mechanism of action of the protease inhibitor suppression of carcinogenesis have focused on the effects of these agents on the expression of specific oncogenes and proteases thought to be involved in the conversion of a cell to the malignant state. Human trials utilizing the soybean-derived protease inhibitor, the Bowman-Birk inhibitor (BBI), as a cancer chemopreventive agent are ongoing. Some of the current laboratory work involves studies on the effects of BBI on surrogate endpoint biomarkers (SEBs) of carcinogenesis in human tissue.
Billings PC, Sanzari JK, Kennedy AR, Cengel KA, Seykora JT: Comparative analysis of colorimetric staining in skin using open-source software. Exp Dermatol 24(2): 157-9, Feb 2015.
Kennedy AR, Crucian B, Huff JL, Klein SL, Morens D, Murasko D, Nickerson, CA, Sonnenfeld G: Effects of sex and gender on adaptation to space: immune system. J Womens Health (Larchmt) 23(11): 956-8, Nov 2014.
Ni J, Romero-Weaver AL, Kennedy AR: Potential Beneficial Effects of Si-Wu-Tang on White Blood Cell Numbers and the Gastrointestinal Tract of gamma-Ray Irradiated Mice. Int J Biomed Sci. 10(3): 182-90, Sep 2014.
Billings PC, Romero-Weaver A, Kennedy AR: Effect of gender on the radiation sensitivity of murine blood cells. Gravitational and Space Biol. 2(1): 25-31, Aug 1 2014.
Romero-Weaver AL, Lin L, Carabe-Fernandez A, Kennedy AR: Effects of Solar Particle Event-Like Proton Radiation and/or Simulated Microgravity on Circulating Mouse Blood Cells. Gravit Space Res. 2(1): 42-53, Aug 2014.
Yoo SS1, Jorgensen TJ, Kennedy AR, Boice JD Jr, Shapiro A, Hu TC, Moyer BR, Grace MB, Kelloff GJ, Fenech M, Prasanna PG, Coleman CN.: Mitigating the risk of radiation-induced cancers: limitations and paradigms in drug development. J Radiol Prot. 34(2): R25-52, Jun 2014.
Lin L, Solberg TD, Carabe A, Mcdonough JE, Diffenderfer E, Sanzari JK, Kennedy AR, Cengel K: Pencil beam scanning dosimetry for large animal irradiation. J Radiat Res May 22 2014.
Krigsfeld GS, Savage AR, Billings PC, Lin L, Kennedy AR: Evidence for radiation-induced disseminated intravascular coagulation as a major cause of radiation-induced death in ferrets. Int J Radiat Oncol Biol Phys. 88(4): 940-6, Mar 2014.
Sanzari JK, Romero-Weaver A, Krigsfeld GS, James G, Lin L, Diffenderfer ES, Kennedy AR: Ground-based microgravity and proton radiation exposure alters leukocyte activity. J Radiat Res. 55 Suppl 1: i94, Mar 2014.
Kennedy AR, Weissman D, Sanzari JK, Krigsfeld GS, Wan XS, Romero-Weaver AL, Diffenderfer ES, Lin L, Cengel K.: Acute effects of solar particle event radiation. J Radiat Res. 55 Suppl 1: i66-i67, Mar 2014.
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Last updated: 02/11/2015
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