KY EPSCoR: A Paradigm-Shifting Therapy for Humans Exposed to Radiation

Ionizing radiation exposure is known to dramatically increase the level of reactive oxygen species (ROS) in human cells. ROS have been implicated as key contributors to numerous pathophysiological disorders including cancer, heart failure, neuro-degeneration, etc., via stimulating autophagy, death, DNA damage, mitochondrial dysfunction or protein deactivation within cells. In recent years, antioxidants, such as curcumin (CCM), N-acetyl cysteine (NAC), and N-mercaptopropionyl glycine (NMPG), have been discovered to neutralize free radicals and protect cells from the insult-induced damage. With NASA’s current interests in returning to the moon and missions to Mars, astronauts would be exposed to increased amounts of ionizing radiation due to the long durations of flights. Thus, this project seeks to use novel drug delivery systems for efficient uptake of CCM, NAC, and N-MPG into cells: 1) fusogenic liposomes –constructed from the same biomaterials that constitute cell membranes; 2) albumin – the most abundant blood protein; and, 3) chitosan – a FDA-approved polysaccharide. These particle systems will be used to investigate drug release, uptake in cells, and effectiveness (such as cell viability and protein expression of DNA damage and repair). Cells and animals will be exposed to either gamma radiation or high-energy iron-ion radiation at Brookhaven National Laboratory. The proposed drug-delivery systems have the capability to provide short- (minutes) and long-term (hours - days) delivery. A tremendous benefit to our delivery system is the ability to tailor drug therapy to accurately correspond to the level and duration of radiation exposure. All other methodologies have pursued a “one-size fits all” approach, which may not deliver an appropriate dose to mitigate adverse events. Our delivery system will rescue irradiated cells via the introduction of drugs to mitigate the effects of the ionizing radiation. The design of countermeasures for mitigation of oxidative stress damage is crucial for protection of astronaut health. Radiation mitigation research aligns with the Human Exploration and Operations Mission Directorate, directly addressing the Human Research Program of Integrated Research Plan Space Radiation Risk: 1.2 Risk of Acute Radiation Syndromes Due to Solar Particle Events, 1.3 Risk of Degenerative Tissue or Other Health Effects from Radiation Exposure,1.4 Risk of Radiation Carcinogenesis from Space Radiation and Exploration Medical Capability Risk: 1.1 Inability to Adequately Recognize or Treat an Ill or Injured Crew Member. The proposed studies focus specifically on Degenerative Tissue - Gaps Degen #6; Acute Radiation Syndromes – Gaps Acute #7; Radiation Carcinogenesis – Gaps Cancer #8; and Exploration Medical Capability – Gap ExMC #4.22. The proposed work also aligns with KY science and technology strategic plans by proposing space-related research while providing opportunities for education to a diverse group in a multidisciplinary subject area. The proposed work includes training of Ph.D. students and postdoctoral fellows, thus strengthening educational opportunities in STEM fields in KY. The research team consists of 3 females and 3 minority members, strengthening the participation of underrepresented groups. Two of the postdocs are KY natives, which aligns with keeping talent within KY and strengthening the competitive and productive community of academic scientists. In addition, the work is collaboration among the School of Engineering (Bioengineering), School of Medicine (Department of Medicine) and industry (EDS, Inc.), which increases faculty-industry partnerships that have commercial potential while strengthening KY’s science and research capacity in priority STEM areas. In addition, NASA collaborators from JSC will strengthen the linkages between KY researchers and NASA Centers’ R&D programs and missions.