HRR - Task - Variation in CNS damage signaling and blood sentinels of neuropathology after exposure to space radiation.

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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)

Task Book: Entry Unavailable
Principal Investigator: Wyrobek, Andrew

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)

Deliverables (2)

Category: Risk Characterization, Quantification
Subcategory: Evidence or Risk Characterization

Description:
1. The proposed research will provide molecular information on the effects of age at radiation exposure, time of tissue collection after exposure, and effects of genomic background on dose response and thresholds for Central Nervous System (CNS) pathways associated with radiation-damage response and neuropathology. This information will provide time information on early and late neuro-pathological changes associated with vascular damage and inflammation that will support establishment of acute and late (CNS) Permissible Exposure Limits (PELs). Our research plan will identify low-dose thresholds for the expression of unique molecular changes and changes in pathways associated with neuropathology.
2. The proposed proteomic and metabolomic research results will be used to identify CNS subregion-specific responses as well as common radiation responses, and to identify mouse-rat cross-genome-risk biomarkers and pathways for the development of molecular countermeasures. This research will examine the molecular evidence that common pathways are affected by HZE exposure in three CNS subregions of the same animal in cerebral spinal fluid (CSF), cortex and hippocampus. This research will focus on molecular changes and signaling pathways after low dose exposure, with emphasis on molecular changes associated with vascular damage and inflammation.
The knowledge gained in this research project will (a) provide data to compare low-dose tissue response across brain subregions in two rodent species (rats and mice), (b) provide evidence of dose-dependence and persistence of pathways associated with neurotoxicity (e.g., inflammation, vascular damage) across CNS subregions in two species, and (c) inform identification of CNS biomarkers and mechanism-based radioprotective countermeasures.

Internal Customers:
Human Factors and Behavioral Performance
Human Health Countermeasures
Space Radiation
External Customers:
None

Category: Risk Characterization, Quantification
Subcategory: Evidence or Risk Characterization

Description:
CBS Supplement Deliverables
1.Evaluate and apply individual-level data on exposure to space radiation, effect modifiers, biomarkers, and/or behavioral outcomes from NASA-funded research to build and estimate the performance of multivariate models to predict individual-level risks of space radiation on operation-relevant performance in distinct behavioral domains.

Internal Customers:
Human Factors and Behavioral Performance
Human Health Countermeasures
Space Radiation
External Customers:
None

Mappings

Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders

BMed-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.

BMed-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?

BMed-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?

BMed-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?

BMed-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.

Variation in CNS damage signaling and blood sentinels of neuropathology after exposure to space radiation.

Risk of Spaceflight Induced Cardiovascular Disease

CVD-102: Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.

Variation in CNS damage signaling and blood sentinels of neuropathology after exposure to space radiation.

Related Tasks (367)

Common Item(s)
	Risk of Spaceflight Induced Cardiovascular Disease