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.
Paul Billings, Ph.D. (Research Associate), Jenine Sanzari, Ph.D. (Senior Research Investigator), X. Steven Wan, Ph.D. (Senior Research Investigator), Ana Romero-Weaver, Ph.D. (Postdoctoral Fellow), Gabriel Krigsfeld (Graduate Student) and Jin Ni, M.D., Ph.D., Visiting Associate Professor from the Second Medical University in Shanghai (China).
Kennedy AR, Wan XS : Countermeasures for Space Radiation Induced Adverse Effects. Adv Space Res. 48(9): 1460-79, Nov 2011.
Zhou Y, Ni H, Li M, Sanzari JK, Diffenderfer ES, Lin L, Kennedy AR, Weissman D: Effect of solar particle event radiation and hindlimb suspension on gastrointestinal tract bacterial translocation and immune activation. PloS one 7(9): e44329, Sep 2012.
Krigsfeld GS, Sanzari JK, Kennedy AR
: The effects of proton radiation on the prothrombin and partial thromboplastin times of irradiated ferrets. Int J Radiat Biol. 88(4): 327-34, Apr 2012.
Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, Purdy JA, Applegate K, Yahalom J, Constine LS, Gilbert ES, Boice JD Jr.: Second malignant neoplasms and cardiovascular disease following radiotherapy. J Natl Cancer Inst. 104(5): 357-70, Mar 7 2012.
Gridley DS, Freeman TL, Makinde AY, Wroe AJ, Luo-Owen X, Tian J, Mao XW, Rightnar S, Kennedy AR, Slater JM, Pecaut MJ.
: Comparison of proton and electron radiation effects on biological responses in liver, spleen and blood.
Int J Radiat Biol. 87(12): 1173-81, Nov 2011.
Kennedy AR, Ware JH, Carlton W, Davis JG: Suppression of the later stages of radiation-induced carcinogenesis by antioxidant dietary formulations.
Radiat Res. 176(1): 62-70, Jul 2011.
Wilson JM, Sanzari JK, Diffenderfer ES, Yee SS, Seykora JT, Maks C, Ware JH, Litt HI, Reetz JA, McDonough J, Weissman D, Kennedy AR, Cengel KA
: Acute biological effects of simulating the whole-body radiation dose distribution from a solar particle event using a porcine model.
Radiat Res. 176(5): 649-59, Nov 2011.
Sanzari JK, Wilson JM, Wagner EB, Kennedy AR: The combined effects of reduced weightbearing and ionizing radiation on splenic lymphocyte population and function. Int J Radiat Biol. 87(10): 1033-8, Oct 2011.
Wilson JM, Krigsfeld GS, Sanzari JK, Wagner EB, Mick R, Kennedy AR : Comparison of hindlimb unloading and partial weight suspension models for spaceflight-type condition induced effects on white blood cells. Adv Space Res. 49: 237-48, Sep 2012.
Mettler FA Jr, Brenner D, Coleman CN, Kaminski JM, Kennedy AR, Wagner LK : Can radiation risks to patients be reduced without reducing radiation exposure? The status of chemical radioprotectants. Am J Roentgenol. 196(3): 616-8, Mar 2011.
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Last updated: 09/25/2013
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