Task Variation in CNS damage signaling and blood sentinels of neuropathology after exposure to space radiation.
Last Published:  03/26/21 03:34:00 PM (Central)
Short Title: CBS CNS Damage Signaling Neuropathology (Wyrobek)
Responsible HRP Element: Human Factors and Behavioral Performance
Collaborating Org(s):
Human Health Countermeasures (HHC) Element
Space Radiation (SR) Element
Funding Status: Active - Currently funded and in progress
Procurement Mechanism(s):
NIPR
Aims:
Original Study Aims
Aim 1. Characterize the persistence of radiation-induced molecular abnormalities in cortex and hippocampus after low-dose exposures to 56Fe particles, and compare the predictions for CNS tissue damage and late-onset neuropathologies in similarly irradiated mice and rats.
Aim 1a: Use archived CNS tissue from SD rats collected at 4 and 9 months after low-dose exposures, and generate new transcriptomics (3’TAGseq) and new metabolomics profiles (untargeted metabolism and targeted complex lipids) from cortex and hippocampus. These data will be integrated with prior proteomics profiles from hippocampus at 9 months after exposure to build a predictive model of CNS tissue damage and risks for neuropathology, with emphasis on vascular and immune abnormalities.
Aim 1b: Compare molecular responses in cortex and hippocampus of mice and rats at 9 months after exposure to evaluate cross- species consistency. The predictive model will be built using integrating bioinformatics and biostatistical approaches.
AIM 2. Identify persistent bio-effect markers in peripheral blood and CSF that correlate with molecular damage in CNS vascular or immune functions.
Aim2A will investigate the metabolomics profiles of archived CSF and archived peripheral blood plasma for the same animals. 
AIM 2B will determine whether the blood metabolites associated with CNS tissue damage correlate with individual variation in radiation-susceptibility for anxiety as measured in the elevated plus maze.

CBS Supplement Aims

Aim 1. Characterize and build computational models for the effects of age-at-exposure and dose

fractionation (repeated exposures) on performance in each of three behavioral domains, using

NASA-provided data sets.

Aim 1a. Evaluate the age-at-exposure and dose fractionation data sets for data quality across ions, exposure regimens, study design, and behavioral outcomes, and for suitability for multivariate modeling of risks for specific behavioral domains.

Aim 1b. Build single-ion risk models that incorporate age-at-exposure and dose-fractionation effects for each behavioral domain, using data sets that pass the Aim 1a evaluation criteria.

Aim 1c. Build multi-ion risk models that integrate the age-at-exposure and dose-fractionation effects for each behavioral domain from the single ion models of Aim 1b. The risk predictions of the different behavioral domains will be evaluated using both experimental exposure regimens and GCR-relevant estimates for ion spectra and doses.

 

Aim 2. Characterize and build computational models for exposure dose and effect modifiers of performance in three behavioral domains, using NASA-provided data sets.

Aim 2a. Evaluate the dose-response and effect-modifier data sets for data quality across ions, exposure regimens, study design, and behavioral outcomes, and for suitability for multivariate modeling of risks for specific behavioral domains. Effect modifiers to be assessed may include strain/genotype, sex, and diet group, depending on the data sets provided.

Aim 2b. Build single-ion risk models that incorporate dose-response and effect-modifier effects for each behavioral domain, using data sets that pass the Aim 2a evaluation criteria.

Aim 2c. Build multi-ion risk models that incorporate dose-response and effect-modifier effects for each behavioral domain, based on the findings of the single ion models of Aim 2b. The risk predictions of the different behavioral domains will be evaluated using both experimental exposure regimens and GCR-relevant estimates for ion spectra and doses.

 

Aim 3. Apply advanced statistical methods to integrate the risk estimates from Aim 1 and Aim 2 into a unified model to predict individual-level risk for specific behavioral domains.

 

Aim 4. Evaluate NASA-provided data sets for building computational models for associations of

CNS tissue biomarkers with performance in three behavioral domains.

Aim 4a. Evaluate the CNS tissue biomarker and behavioral outcomes data set for data quality across exposure regimens and behavioral outcomes, and for suitability for multivariate modeling of risks for specific behavioral domains. Effect modifiers that maybe available include strain/genotype and age at exposure. The data sets expected to be available for aim 4 are likely to be single ion experiments with molecular biomarker data from a few CNS sub-regions in animals tested for behavioral outcomes.

Aim 4b. Build single-ion risk models for CNS tissue biomarkers for each behavioral domain, using data sets that pass the Aim 4a evaluation criteria

Resources (None Listed)
Mappings
RiskRisk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
GapBMed-101: We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
GapBMed-102: Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions?
GapBMed-103: What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions?
GapBMed-107: What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews?
GapBMed-108: Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
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RiskRisk of Spaceflight Induced Cardiovascular Disease
You are here!TaskVariation in CNS damage signaling and blood sentinels of neuropathology after exposure to space radiation.