GSAM project provides delivery scheme of low and high LET particles to best simulate 600/900 day Mars missions within facility and animal constraints.

• Studies required to inform countermeasure testing and validation
• Fluence based versus acute exposures to simulate space radiation 

GSAM (GCR Simulation and Mitigation) research objectives:

Aim 1:  Design and implement Hybrid Shield Concept to simulate GCR environment at NSRL to include production of secondaries and correlated multiplicities found in space

Aim 2:  Validate ground simulation of dose rate including fractionation and time course delivery of particles to simulate low dose chronic exposures in space.  

Aim 3: Evaluation of dose delivery scheme with biological timescales to inform chronic studies.

Aim 4: Expand design and implement Mars surface simulation at NSRL to include mixed field environment found on Mars surface.

Specific Aim 1: Determine the efficacy of γ-tocotrienol as a countermeasure against mixed

charged particle radiation-induced carcinogenesis.

Specific Aim 2: Determine the effects of γ-tocotrienol on mixed charged particle

radiation-induced degenerative effects on the central nervous system.

Specific Aim 3: Determine the effects of γ-tocotrienol on mixed charged particle

radiation-induced degenerative effects on the cardiovascular system.

• Aim 1 (CVD): Validate surrogate endpoint biomarkers, including standard of care clinical markers, for monitoring space radiation-induced late cardiovascular diseases for use in risk assessment model development and evaluation of protective countermeasures.

• Aim 2 (Late CNS): Define adverse outcome pathways and potential biomarkers associated with CNS functional changes and late neurodegenerative diseases

• Aim 3 (CVD): Evaluate standard of care clinical protective measures, such as exercise, dyslipidemia drugs, anti-inflammatory drugs, diet, as mitigation strategy for late cardiovascular diseases.

• Aim 4 (late CNS): Determine whether CVD countermeasures are effective in mitigating adverse CNS effects.

• Aim 1 (CVD):  Validate efficacy of standard of care clinical protective measures in a combined stressor model with chronic mixed field exposures, evaluating for mitigation of radiation-induced CVD.

• Aim 2 (CVD/CNS): Validate efficacy of cross-risk candidate radioprotective agents in a combined stressor model with chronic mixed field exposures, evaluating for mitigation of radiation-induced CVD and late CNS adverse outcomes.

• Aim 3 (CVD, CNS):  Evaluate any potential antagonistic, synergistic, or additive effects across CVD protective measures and late CNS adverse outcomes.

Research will evaluate medical countermeasures that mitigate risk of radiation induced diseases addressing multiple tumor types and multiple risk areas (i.e., cancer, late neurodegeneration, cardiovascular disease) including the:

• Mitigation of solid and hematologic cancers due to space radiation exposure as measured by incidence, aggressiveness, overall burden, and time to occurrence.

• Mitigation of cardiovascular disease incidence, latency, and progression as measured by clinical outcomes, events, pathology and survival times.

   

• Mitigation of late neurodegenerative conditions and microvascular disruption of the CNS as measured by changes in performance, cognitive function, and pathology.

Specific Aims:

• Aim 1 (Cross Risk): Identify and prioritize candidate cross-risk countermeasure agents targeting common pathways of adverse outcomes from space radiation exposure

• Aim 2 (Cross Risk): Using appropriate animal models, test efficacy of selected medical countermeasures for prevention of adverse outcomes across multiple risk areas following simulated GCR and SPE exposures.

• Aim 3 (Cross Risk): Identify potential cross-risk and cross-element antagonistic countermeasure approaches

• Aim 4 (Cross Risk): Identify biomarker approaches to assess countermeasure efficacy for surveillance, treatment, and outcome prediction.

Specific Aims:

• Aim 1: Identify and prioritize candidate radioprotective and chemopreventive agents to mitigate radiation health risks

• Aim 2: Perform preliminary countermeasure evaluation using radioprotective/chemopreventive agents that target common pathways of radiation induced injury (e.g. inflammation).

• Aim 3: Test efficacy of selected medical countermeasures in space relevant environments.

Studies to validate identified medical countermeasures that address multiple tumor types and multiple risk areas (i.e., cancer, late neurodegeneration, cardiovascular disease) with the following aims:

Specific Aims:

• Aim 1 (Cross Risk): Validate efficacy of candidate countermeasure agents in additional model systems in compliance with FDA animal rules.

• Aim 2 (Cross Risk): Validate efficacy of candidate countermeasure agents in space relevant environment.

• Aim 3 (Cross Risk):  Determine minimum dosing (mg/day) requirements for optimum effectiveness.

• Aim 4 (Cross Risk):  Evaluate any potential antagonistic effects across space radiation risk area endpoints including multiple tumor types

• Aim 5 (Cross Risk): Evaluate biomarker approaches to assess countermeasure efficacy for surveillance, treatment, and outcome prediction.

Robust identification of current research that identifies both pre-mission risks and vulnerabilities for individuals due to family history, previous exposures, preventive medicine, sensitivites, genotype and phenotype within the context of integrated risk and risks posed to crew health and safety and the countermeaaures needed should medical conditions arise.  For example, in major depressive disorder, high levels of histone deacetylase 5 prior to treatment initiation appear to be a robust marker for treatment response (Iga et al., 2007; Hobara et al., 2010; Belzeaux et al., 2010). Levels of cyclic-adenosine monophosphate (cAMP) response element binding protein 1 (Iga et al., 2007), histone deacetylase 2 (Hobara et al., 2010), serotonergic markers (Belzeaux et al., 2010), a panel of four gene expression pro les (Belzeaux et al., 2012), and interferon regulatory factor 7 (Mamdani et al., 2011) have variously been reported to change following treatment with antidepressants.

-Belzeaux R, Formisano-Tre´ziny C, Loundou A, Boyer L, Gabert J, Samuelian JC, Fe´ron F, Naudin J, Ibrahim EC (2010) Clinical variations modulate patterns of gene expression and de ne blood biomarkers in major depression. J Psychiatr Res 44:1205–1213.
-Belzeaux R, Bergon A, Jeanjean V, Loriod B, Formisano-Treziny C, Verrier L, Loundou A, Baumstarck-Barrau K, Boyer L, Gall V, Gabert J, Nguyen C, Azorin JM, Naudin J, Ibrahim EC (2012) Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl Psychiatry 2:e185.
-Hobara T, Uchida S, Otsuki K, Matsubara T, Funato H, Matsuo K, Suetsugi M, Watanabe Y (2010) Altered gene expression of histone deacetylases in mood disorder patients. J Psychiatr Res 44:263–270.
-Iga Ji, Ueno Si, Yamauchi K, Numata S, Kinouchi S, Tayoshi- Shibuya S, Song H, Ohmori T (2007) Altered HDAC5 and CREB mRNA expressions in the peripheral leukocytes of major depression. Prog Neuropsychopharmacol Biol Psychiatry 31:628–632.
-Mamdani F, Berlim MT, Beaulieu MM, Labbe A, Merette C, Turecki G (2011) Gene expression biomarkers of response to citalo- pram treatment in major depressive disorder. Transl Psychiatry 1:e13.