HRR - Gap - CVD-202: Develop and ground-test countermeasures against the spaceflight-induced changes in the cardiovascular system of importance for development of disease.

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CVD-202: Develop and ground-test countermeasures against the spaceflight-induced changes in the cardiovascular system of importance for development of disease.

Content in this Gap was split from 1 other Gap

Last Published: 07/30/21 01:05:31 PM (Central)

Responsible Element: Human Health Countermeasures (HHC)

Status: Open

Description

Present state of knowledge: Mitigation of cardiovascular disease risk factors associated with spaceflight exposure (e.g., reduced physical activity, poor dietary habits, circadian dysregulation, impaired sleep, immune dysregulation, psychological stress, elevated levels of oxidative stress, and inflammation) would be appropriate avenues to control the risk of cardiovascular disease during and after spaceflight. For example, in a bed rest model, exercise alone was able to prevent carotid artery remodeling that was present in control subjects who performed no exercise. In addition to the inflight habits encouraged during spaceflight (e.g., exercise, appropriate dietary choices, improved sleep habits, managing psychological stress), countermeasures might include dietary and pharmacological interventions that have shown promise in ground-based research, such as sulfhydryl or thiol compounds, anti-oxidants, anti-inflammatories, and cholesterol level-modifying medications (e.g., statins and γ-tocotrienol).

Research approach: Testing effects of countermeasures (e. g. anti-oxidants, pharmaceuticals, nutrition) in rodents and larger animals during suspension combined with NSRL radiation.

Target for Closure

Understanding which countermeasures are effective and, when possible, test synergistic effects of multiple countermeasures. The purpose is to understanding which countermeasure combinations will be operationally-feasible during spaceflight.

Validation of countermeasures in a chronic mixed field environment in accordance with the FDA Animal Rule.
Evaluation of countermeasures in a combined stressors model in a chronic mixed field environment.

Mappings

Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes

CVD-202: Develop and ground-test countermeasures against the spaceflight-induced changes in the cardiovascular system of importance for development of disease.

Active

Attenuation of Space Radiation-induced Pro-oxidant and Fibrotic Signaling in the Heart by Nutritional and Genetic Interventions: Adventures in Tissue Sharing

Task Book: Entry
Principal Investigator: Lawler, John

Short Title: Tissue-Oxidative and Fibrotic

Responsible HRP Element: Space Radiation

Collaborating Org(s):

Human Health Countermeasures (HHC) Element

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

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.

Resources (None Listed)

Deliverables (1)

Gamma-tocotrienol as a countermeasure against high-energy charged particle-induced carcinogenesis, cardiovascular disease, and central nervous system effects

Task Book: Entry
Principal Investigator: Boerma, Marjan

Short Title: Gamma-tocotrienol as a Radiation Countermeasure

Responsible HRP Element: Space Radiation

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

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.

Resources (None Listed)

Deliverables (1)

Category: Countermeasure
Subcategory: Clinical Procedure/Prescription

Description:

The proposed studies will address the Gaps Cancer 08, Degen - 6, and CNS - 4 by providing

a systematic analysis of γ-tocotrienol as a safe oral countermeasure against mixed charged

particle-induced carcinogenesis and degenerative effects in the heart, brain and vasculature (see

also 4. Map to Human Research Roadmap). The Countermeasure Readiness Level (CRL) at the

start of the project will be 4 (“Formulation of countermeasure concept based on understanding of

phenomenon”), and at the completion of the study will be 5 (“Proof of concept testing and initial

demonstration of feasibility and efficacy”). Since γ-tocotrienol is being evaluated in clinical

trials of radiation therapy, and its safety profile is high, we anticipate that the CRL can be

advanced quickly into human space flight conditions once efficacy against high-energy charged

particle irradiation is documented in animal models. This will also be one of the first studies to

provide a systematic analysis of carcinogenesis and degenerative tissue effects after exposure to

a mixed ion beam. Although hind limb unloading to model fluid shifts from exposure to

microgravity is not part of this proposal, we have experience with this model and can test γ-

tocotrienol in a combined radiation and hind limb unloading model in the future.

Internal Customers:
None External Customers:
None Is a Customer-Supplier Agreement (CSA) Required? No

Completed

Center for Research on Cardiac and Vascular Effects of Space Radiation

Task Book: Entry
Principal Investigator: Boerma, Marjan

Short Title: Center for Cardiac & Vascular

Responsible HRP Element: Space Radiation

Collaborating Org(s):

National Space Biomedical Research Institute (NSBRI)

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Solicited

Aims:
Acute:

Specific Aim 1: Define the acute effects of low-dose proton irradiation on the hematopoietic system, skin, heart, and retina.
Specific Aim 2: Examine acute effects of low-dose proton irradiation in combination with modeled microgravity on the hematopoietic system, skin, heart, and retina .
Specific Aim 3: Evaluate the acute effects of low-dose proton irradiation on the adaptive immune response.
Specific Aim 4: Test whether γ-tocotrienol protects against acute effects of low-dose proton irradiation.

Degenerative:
Specific Aim 1: Determine the effects of low-dose 56Fe and proton irradiation on cardiac and vascular function and structure.
Specific Aim 2: Identify acute and chronic biomarkers of cardiovascular dysfunction after low-dose 56Fe and proton irradiation.
Specific Aim 3: Elucidate the role of metabolic changes in the cardiovascular response to low-dose 56Fe and proton irradiation.
Specific Aim 4: Determine the effects of radiation dose and quality on endothelial cell functional phenotype and markers of endothelial dysfunction.
Specific Aim 5: Investigate whether γ-tocotrienol protects against cardiovascular effects of low-dose high LET radiation.

Resources (None Listed)

Deliverables (1)

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

Description:

Recent evidence strongly suggests that humans will face increased risks for adverse effects on heart and blood vessels from radiation exposure during space travel; however, these risks are not well defined. The proposed Center for Research on Cardiac and Vascular Effects of Space Radiation comprises teams from four institutions with experts in the fields of space radiation, cardiovascular radiation injury, and modern techniques of molecular analysis. The goal is to characterize the cardiovascular risks of space radiation. Studies will begin with mouse models and then proceed to rabbits to enhance translation to the human situation. Animals will be exposed to accelerated charged particles relevant to radiation in interplanetary space, and monitored for up to 9 months comparable to many years observation in humans. Heart function will be measured non-invasively at regular intervals with high-resolution ultrasound. Heart tissue will be obtained at different time points to investigate pathological changes, including scar tissue and inflammation. Cutting-edge molecular techniques will be used to examine thousands of proteins and DNA segments to understand mechanisms of radiation injury and aid in the discovery of sensitive biomarkers. We will also examine blood vessels in the heart and the retina of the eye, based on evidence that space radiation causes changes in the retinal blood vessel network, similar to those associated with reduced vision due to aging. Sensitive staining techniques will be used to reconstruct the structure of blood vessels in the retina and heart. Lastly, we will test whether gamma-tocotrienol, a safe dietary antioxidant and the strongest natural product radiation protector yet discovered, will reduce the effects of space radiation on heart and blood vessels. Altogether, these studies use innovative methods to characterize acute and degenerative cardiovascular effects of space radiation, and will help develop safe and effective countermeasures to protect humans against these effects.

Internal Customers:
None External Customers:
None Is a Customer-Supplier Agreement (CSA) Required? No

Candidate nutritional countermeasure to mitigate adverse effects of spaceflight (Schreurs)

Task Book: Entry
Principal Investigator: Schreurs, Ann-Sofie

Short Title: Dried plum countermeasure

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Solicited

Aims:

Determine if the antioxidant rich diet Dried Plum (DP) diet prevents simulated microgravity-induced bone loss.

Determine if DP prevents simulated spaceflight-induced bone loss (microgravity and radiation combined).

Determine if DP is effective as a countermeasure for adverse effects of simulated microgravity and radiation on non-skeletal tissues (brain, eye).

Resources (None Listed)

Deliverables (1)

Mitigating radiation-induced bone loss via dietary modulation of inflammatory cytokines (Bloomfield)

Task Book: Entry Unavailable
Principal Investigator: Bloomfield, Susan

Short Title: radiation bone resorption dietary CM

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Solicited

Aims:

Determine alterations in bone structural integrity (density, geometry,

microarchitecture, mechanical properties), bone cell activity and osteocyte TNF-α, RANKL,

and sclerostin in mice exposed to low dose HZE radiation.

Determine impact of a diet high in omega-3 fatty acid content on osteocyte

TNF-α and decrements in bone structural integrity after exposure to low dose HZE radiation.

Resources (None Listed)

Deliverables (1)

Planned-Funded

2020 Cross-Species Rodent ISS Study: CVD/late CNS Clinical Model #1 (chronic study)

Task Book: Entry Unavailable
Principal Investigator: TBD

Short Title: CVD Rodent ISS

Responsible HRP Element: Space Radiation

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:

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

Resources (None Listed)

Deliverables (1)

Multi-Disciplinary Research Plans

Documentation:

No Documentation Available

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Risk Approach Plans (1)

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Common Item(s)
	Mitigating radiation-induced bone loss via dietary modulation of inflammatory cytokines (Bloomfield)