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Project Title:  VNSCOR: Responses of the Nervous System to Chronic, Low Dose Charged Particle Irradiation Expand All
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HFBP:Human Factors & Behavioral Performance (IRP Rev H) 
Start Date: 04/15/2018  
End Date: 11/02/2022  
Task Last Updated: 01/30/2019 
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Principal Investigator/Affiliation:   Nelson, Gregory A. Ph.D. / Loma Linda University 
Address:  Basic Sciences, Div. Radiation Research 11175 Campus Street 
Chan Shun Pavilion, Room A-1024 
Loma Linda , CA 92350-1700 
Email: grnelson@llu.edu 
Phone: 909-558-8364  
Congressional District: 31 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Loma Linda University 
Comments:  
Co-Investigator(s) / Affiliation:  Hartman, Richard  Ph.D./ Loma Linda University  Mao, Xiao Wen  M.D./ Loma Linda University  Rosi, Susanna  Ph.D./ University of California, San Francisco  Vlkolinsky, Roman  Ph.D./ Loma Linda University 
  Wroe, Andrew  Ph.D./ Loma Linda University 
Project Information: Grant/Contract No. 80NSSC18K0785 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.williams-1@nasa.gov 
Solicitation: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC18K0785 
Project Type: GROUND  
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Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
 (2) HFBP CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev J)
 (3) Sensorimotor (SM):Risk of Impaired Control of Spacecraft, Associated Systems and Immediate Vehicle Egress Due to Vestibular/Sensorimotor Alterations Associated with Space Flight
Human Research Program Gaps: (1) BMed02:We need to identify and validate measures to monitor behavioral health and performance during exploration class missions to determine acceptable thresholds for these measures (IRP Rev F)
 (2) CBS-CNS - 3:How does individual susceptibility including hereditary pre-disposition (e.g. Alzheimer’s, Parkinson’s, apoE allele) and prior CNS injury (e.g. concussion, chronic inflammation or other) alter significant CNS risks? Does individual susceptibility modify possible threshold doses for these risks in a significant way? (IRP Rev G)
 (3) CBS-CNS-5:How can new knowledge and data from molecular, cellular, tissue and animal models of acute CNS adverse changes or clinical human data, including altered motor and cognitive function and behavioral changes be used to estimate acute CNS risks to astronauts from GCR and SPE? (IRP Rev F)
 (4) CNS01:What are significant adverse changes in CNS performance in the context and time scale of space flight operations? How is significance defined, and which neuropsychological domains are affected? Is there a significant probability that space radiation exposure would result in adverse changes? What are the pathways and mechanisms of change? (IRP Rev F)
 (5) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
 (6) CNS08:Are there significant CNS risks from combined space radiation and other physiological or space flight factors (e.g., sleep deprivation, psychological, microgravity, immune-endocrine systems or other)?
 (7) SM24:SM24: Determine if the individual capacity to produce adaptive change (rate and extent) in sensorimotor function to transitions in gravitational environments can be predicted with preflight tests of sensorimotor adaptability (IRP Rev F)
 (8) SM26:Determine if exposure to long-duration spaceflight leads to neural structural alterations and if this remodeling impacts cognitive and functional performance (IRP Rev F)
Task Description: [Ed. note Jan 2019: See also project, "VNSCOR: Mechanisms of Radiation-Induced Changes in Sustained Attention and Social Processing" (PI: Catherine Davis)]

NELSON/DAVIS VIRTUAL NASA Specialized Center of Research (NSCOR): The project is an combined experimental campaign combined with "Mechanisms of Radiation-Induced Neurobehavioral Defictis (PI: Davis) (see above for official project title) to quantify responses for an interrelated set of central nervous system (CNS) outcome measures in mice to acute and protracted exposures to protons at a dose of 0.5 Gy and sham controls; acute and protracted exposures to 0.25 and 0.5 Gy of charged particles; and acute and protracted exposures to 0.5 and 1.5 Gy of gamma rays. All proposed work will use wild type mice and will be performed under Institutional Animal Care and Use Committee (IACUC) approved protocols in Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-certified facilities at Loma Linda University (LLU), the University of California (UCSF), and Brookhaven National Laboratory (BNL). For all three specific aims the species is Mus musculus, strain C57Bl/6J. Ages are 5 - 6 months at acquisition and the beginning of 42 day irradiation procedures. Sexes are males and females. Scheduled sacrifices are at 1 week, 30 days, 90 days, 6 months, and 12 months post-irradiation. Behavioral testing will occur prior to the use of the same animals for terminal assays. All outcome measures will be quantified in males (N=960) and a subset of measures less prone to sex-dependent variability will be quantifies in females (N=220) for a total of N = 1180.

ORIGINAL PROPOSAL DESCRIPTION: Evidence has accumulated from animal studies that the central nervous system (CNS) undergoes deleterious changes after exposure to charged particle radiation such as protons and high atomic number atomic nuclei that are found in space as galactic cosmic rays and solar particle events. Observed changes include inflammation, oxidative stress, loss of neuron (dendrite) branches and connections (synapses), altered signaling molecules, altered electrical properties, loss of blood vessels, and impaired behavioral performance. If humans respond to charged particles in the same way as animals, then it is possible that deleterious changes may be sufficient to cause cognitive and other behavioral impairments that could compromise spaceflight missions and astronaut health.

The current evidence is based primarily on short exposures to single radiation types. However, space radiation is a complex mixture of these particles and exposures accumulate gradually over the course of missions. It is well established in radiation biology that reduction of the dose rate can have a profound effect on the outcome. Therefore, to better simulate the space environment, we propose to expose adult mice to either 0.5 Gy protons or 0.25 and 0.5 Gy mixtures of helium, oxygen, and silicon particles in 2:1:1 ratios as they are found in space. Then we will deliver the exposures over long time periods (up to 6 weeks) in multiple short exposures (fractions) compatible with particle accelerator operations. These results would be compared to results from acute exposures to establish the Dose Rate Effectiveness Factors (DREFs) which are needed for risk estimation for astronaut health. We predict that the high numbers (fluence) of protons will result in multiple traversals of cells within short times that may elicit interacting biological responses, whereas the lower fluence of higher charged ions will result in rare independent events. DREFs > 1 are predicted for protons and DREFs ~1 are predicted for high Z particles.

We will also compare the "protracted" exposures of charged particle mixtures to gamma rays to determine whether they have equivalent dose effects or are more effective. The relative biological effectiveness factor (RBEs) will be derived. These RBEs are utilized in predicting densely ionizing radiation effects in humans for whom only gamma ray and X-ray data are available with the assumption that the ratios obtained in animal models are realistic surrogates for humans.

We will test both male and female animals as their responses are not identical and the astronaut population is of mixed gender. For each of the exposure regimens we will conduct a battery of behavior tests, measure electrophysiological properties in tissue slices, and quantify changes in the structure and composition of the tissue using state of the art biochemical, histochemical, and microscopy methods. This will allow us to identify the underlying physiological changes most sensitive to dose rate and radiation quality and how they combine to produce behaviors that are adaptive or maladaptive. Together the data generated by the project will enhance NASA's ability to translate animal assessments of CNS structure and function to humans, and to update risk estimates based on single radiation species, high dose rate irradiation protocols, to higher fidelity space-like exposures of charged particle mixtures delivered at dose rates approaching those observed in space.

 

Research Impact/Earth Benefits:

 

Task Progress & Bibliography Information FY2018 
Task Progress: New project for FY2018.

 

Bibliography Type: Description: (Last Updated: 10/30/2019)  Show Cumulative Bibliography Listing
 
 None in FY 2018