Aim 1: To determine the effects of X-ray radiation on RAS, pro-oxidant and pro-fibrotic markers in the heart. The proposal hypothesizes that the combination of fish oil with pectin will mitigate radiation-induced pathology.

Aim 2: The impact of HZE (28Si, 48Ti) radiation on cardiac markers of pro-oxidant and pro-fibrotic signaling will be determined. This proposal postulates that intervention with fish oil and pectin will abrogate radiation-induced oxidative stress and fibrosis in the heart.

Aim 3: The effect of HZE (56Fe) radiation combined with X-Ray radiation at BNL will be determined on RAS, oxidative stress, pro-inflammatory markers, and pro-fibrotic signaling on heart. The proposal hypothesizes that deletion of a single p53 allele will significantly affect markers of oxidative stress, inflammation, and fibrosis.

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.

Focus of this research is the evaluation of the effects of the combined exposures (weightlessness plus radiation) on cardiovascular structure and function.

Specific Aims:

• Aim 1: Utilize a ground-based rodent animal model involving hindlimb suspension as a simulation of weightlessness combined with radiation exposures

• Aim 2: Evaluate potential oxidative and inflammatory biomarkers as surrogate endpoints and compare with available human data from ISS missions

• Aim 3: Evaluate effects of combined exposures on disease latency and progression

• Aim 4: Investigate effects of countermeasures for mitigation of the simulated deep space effects

• Aim 5: Validate ground analogs with flight cohorts

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.