Radiation Countermeasures (USUHS)
Abstract
For the Uniformed Services University of the Health Sciences (USU), this program supports developmental, mission directed research to investigate new concepts and approaches that will lead to advancements in biomedical strategies for preventing and treating the health effects of human exposure to ionizing radiation as well as radiation combined with injuries (burns, wounds, hemorrhage), termed combined injury (CI). Research ranges from exploration of biological processes likely to form the basis of technological solutions, to initial feasibility studies of promising solutions. Program objectives focus on preventing and mitigating the health consequences from exposures to ionizing radiation, in the context of probable threats to U.S. forces in current tactical, humanitarian and counterterrorism mission environments. New protective and therapeutic strategies will broaden the military commander's options for operating within nuclear or radiological environments by minimizing both short-and long-term risks of adverse health consequences. FY 2018 Plans: -Test and evaluate five or more new compounds in mouse model for the development of new radiation protection (prophylactic) countermeasures. -Conduct mechanism of action studies to elucidate the cell signaling transduction pathways for promising drug substances and products as potential radiation countermeasures using cell-based assays for their characterization. -Conduct animal studies to evaluate BBT-059, a PEGylated protein analog in a mouse model for radiation countermeasures development. -Test and evaluate promising drug substances and products as radiation countermeasures to determine their efficacy and safety in irradiated gut and/or lung mouse model used for studying radiation biology. -Evaluate long term effects of acute radiation exposure in surviving mice after exposure to lethal dose of radiation. -Evaluate survival effects of ghrelin as a drug substance for radiation treatment in animal model for acute radiation syndrome (ARS). -Continue to evaluate and down-select lead drug substances and products and drug combinations that are effective at radiation doses producing hematopoietic (H-ARS) or gastrointestinal (GI-ARS) syndrome and identify those that are effective in treating radiation combined (e.g. burn, wound, etc.) injury in animal model of ARS. -Test and evaluate drug substances and products for radiation countermeasures development against mixed-field (neutron and photon) radiation exposure mimicking those from an improvised nuclear device at relevant distances from the epicenter. -Conduct further studies to elucidate the mechanism of action of promising drug substances and drug products against mixed-field radiation exposure using cell-based assays for their characterization. -Further evaluate radiation sensitivity and variation among different animal models (species). -Conduct exploratory studies on radiation effects when combined with insults from viruses or bacteria on the immune system and elucidate the ensuing reactive oxygen species (ROS) produced by cellular metabolism and how by using broad MAPkinase pharmacological inhibitors, antioxidants and modulators, highly selective inhibitors, etc. provide a potential treatment or drug for the radiation combined insults. -Establish panel of gene reporter cells system and methodologies to identify potential on and off therapeutic biological targets towards a novel strategy for developing new radiation countermeasures. -Continue evaluation of radiation-induced leukemia in murine model to concomitantly predict leukemia development based on epigenetic markers identified previously in FY16 and FY17 at low and high doses of radiation exposure and determine the dual benefit of administering radiation countermeasures (drug substance) for both acute and delayed effects of ionizing radiation exposure. FY 2018 Accomplishments: -Demonstrated that MAPK inhibitors can both increase and decrease production of radiation induced inflammatory cytokines and chemokines secreted by murine macrophages. This broadens the types of regulator interventions potentially available for controlling inflammation. -Published peer reviewed manuscript describing how commercially available gene reporter cells can be used to assay Type I interferons (IFNα/β). Potentially this can be a lower cost method with utility to screening large sample sets or high through put experimental approaches. -Established a material transfer agreement (MTA) with pharmaceutical drug sponsors to test a select list of drug candidates for radiation countermeasures development. -Completed acute toxicity study of four drug candidates. The candidates are (1) EPX-217 from Epitek, Inc, (2) MultiStem from Athersys, Inc., (3) Ketone ester from National Institute of Health, and (4) Xisomab 3G3 from Aronora Inc. These prescreened drug candidates were obtain through an interagency agreement (IAA) with the National Institute of Allergy and Infectious Diseases (NIAID) to test their survival efficacy following total body irradiation (TBI). -Completed acute toxicity study of PLX-R18 (Pluristem therapeutics Inc.) and BP-C2 (Meabco A/S) drug molecules. -Completed thirty day efficacy study with PLX-R18 in H-ARS mouse model, the result shows ~45% survival benefit with the drug. A confirmation study is being planned; recently PLX-R18 has received Investigational new drug (IND) status by FDA. - Completed evaluation of MAPK/ERK (Extracellular Signal-regulated Kinase) signaling pathway, RT²Profiler PCR Array and TGFß / BMP Signaling Pathway. Completed assay of RT² Profiler PCR Array with spleen from irradiated animals with and without the radiation drug candidate (BBT-059) to determine the biological target of BBT-059 in the aforementioned cellular these pathways. -Completed analysis of blood and major organs and tissues including eye and brain harvested at 1, and 6 months post-TBI to a lethal dose of radiation in order to assess DEARE (Delayed effects of acute radiation exposure) in surviving animals treated with two radiation drug candidates (BBT-059 and TPOm). - Completed global profile of cellular gene responses (i.e. transcriptomic changes) in CD34+ cell populations exposed to different doses of ionizing radiation (IR) to determine the gene signature biomarkers for dose-dependent effects of IR for radiation drug. - Reported on the underlying mechanisms of ghrelin as a potential drug to mitigate multi-organ injury involving radiation exposure. The findings shows that Ghrelin can potentially be used as therapeutic for treating radiation injury alone or in combination with physical trauma. Two papers on hematopoietic mitigation and brain bleeding inhibition have been published in Cell Biosci 8:27, 2018 and International Journal of Molecular Science 18:1693, 2017.
Document Details
- Document Type
- Accomplishment
- Publication Date
- Oct 01, 2020
- Source ID
- 848580e8526abfcad1ad036aa93b278c