Initiative funds research to explore how the microbiome affects severity of radiation injury and how the microbiome itself is impacted by exposure to radiation.
Supports development of medical countermeasures (MCMs) targeting the microbiome to mitigate or treat radiation injury.
Radiation injuries can occur as a result of the detonation of conventional explosives combined with radioactive materials e.g., “dirty bombs”, placement of radioactive sources in public locations, contamination of food and water supplies, accidents or attacks on nuclear reactors or sites where radioactive materials are stored, or, in a worst-case scenario, detonation of a nuclear device.
In 2004, the National Institute of Allergy and Infectious Diseases (NIAID) was charged with developing and managing basic and translational research to understand mechanisms of radiation injury; accelerating development of radiation MCMs to mitigate and/or treat acute radiation syndrome (ARS), and delayed effects of acute radiation exposure (DEARE); and supporting research on biomarkers and biodosimetry assays to determine severity of radiation-related injury, information that is necessary for triage and medical decision-making.
The U.S. Food and Drug Administration (FDA) has thus far licensed Neupogen®, Neulasta®, Nplate® (Amgen) and Leukine® (Partner Therapeutics) to treat the hematopoietic (H) sub-syndrome of ARS (H-ARS). Clearly, progress has been made to counteract the immediate effects of H-ARS. However, given the multiple organ injury and inflammation that ensue following radiation exposure, other biological effects must be addressed as well.
High dose radiation exposures can cause gastrointestinal (GI) complications, including mucosal barrier breakdown, bacterial translocation, and loss of GI structural integrity, which can lead to rapid death. Furthermore, victims who survive ARS may suffer from DEARE, which could include pulmonary, renal, cardiac, and cutaneous complications occurring weeks to months or years after radiation exposure. No products are yet approved to treat these other sub-syndromes, and no radiation biodosimetry tests have yet been cleared by the FDA for triage, dose assessment or to predict outcome.
Of particular interest is the impact of irradiation on GI tract, skin, and lung microbiome niches, as well as the microbiome’s potential influence on sensitivity or resilience to radiation injury. Exploring these effects may lead to further identification of microbiome targets for radiation drug development and/or the discovery of microbiome signatures predictive of radiation injury or recovery. Although animal studies in this field are limited, to date they have shown that treatment with antibiotics and altering the gut microbiome composition can influence survival after radiation exposure and that other microbiomes in the body can also have an impact on the radiation response.
Much is still unclear about how the microbiome can influence survival. Conflicting data concerning the role of the microbiome in radiation sensitivity and cell death pathways have revealed knowledge gaps in this area of radiation research. For example, rodent studies suggest that the gut microbiota can promote radiation resilience by protecting the epithelium from apoptotic responses and, in contrast, could also lead to radiosensitivity by inducing endothelial cell apoptotic responses. More research is needed to understand such differences and to harness the potential of the microbiome to aid in the body’s response to radiation.
Animal studies have also shown that the microbiome diversity shifts over time after exposure to radiation, which is important, given that a diverse microbiome has been linked to improved post-irradiation survival. In addition, probiotic bacteria have been studied as delivery vehicles for gut-targeted therapeutics. While intriguing work is already being conducted, more research is needed to fully understand the interplay between the microbiome and survival after radiation exposure.
Research Objectives and Scope
Specific areas of interest for funding under this effort are studies to understand the role of the microbiome in radiation pathogenesis, assessment of exposure, and as a target for mitigation, recovery, and/or exacerbation of injury following radiation exposure. Such studies may help reveal new mechanisms of action and help to identify novel MCMs and biomarkers for biodosimetry to be used in the event of a radiation public health emergency.
Radiation exposures experienced during a radiological or nuclear incident will likely vary from low (1-2 Gy) to high dose and could involve different dose rates and radiation exposure scenarios, such as prompt gamma and neutron irradiation, and/or fallout or internalized radionuclide exposures. Research to understand the complexities of the body’s resident microbiota and their pathogenesis in radiation injury is needed to fill gaps in the knowledge base.
Radiation exposure type, dose level, and dose rates proposed for study should be relevant to what would be anticipated during a radiological or nuclear incident. To advance the state of the science and facilitate research on radiation and the microbiome, NIAID is interested in studies proposing, but not limited to the following:
- Projects addressing the role of microbiome in radiation injury, and development of animal models to study the effects of irradiation on the microbiome in organs/tissues with relevance to a radiation emergency (e.g., GI tract, oral mucosa, skin, lung, etc.), and its involvement in radiation pathogenesis in those tissues and organs affected by total and/or partial body radiation exposure
- Studies of the differing microbiome strains and species linked to susceptibility or resistance to radiation injury
- Development of MCMs targeting the microbiome to mitigate or treat radiation injuries (probiotics, fecal microbiota transplant, antibiotic approaches, other)
- Identification and demonstration of efficacy of MCM candidates targeting the microbiome or the immune system interactions with the microbiome effective when administered at least 24 hours post-irradiation
- Approaches that demonstrate ease-of-use in a mass casualty setting (i.e., route of administration is oral, subcutaneous, intramuscular, inhaled, topical, transdermal, etc.)
- Research on microbial changes following radiation exposure that could be utilized as biomarkers of injury/biodosimeters
- Ex vivo studies using human subject samples
Additional details are available at SAM.gov under RFA-AI-21-068. Applications are due 9 Feb 2022. Scientific merit review begins in July 2022 with earliest research start date to commence in Feb 2023.