HRR - Gap - CVD-103: Determine whether the combined effects of relevant deep-space radiation and weightlessness induce additive or synergistic effects on the cardiovascular system, and whether it is of concern for development of disease.

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CVD-103: Determine whether the combined effects of relevant deep-space radiation and weightlessness induce additive or synergistic effects on the cardiovascular system, and whether it is of concern for development of disease.

Content in this Gap was split from 2 other Gaps

Content in this Gap was merged 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: Only 24 Apollo astronauts have traveled beyond the protection of van Allen Belts and been subjected to the combined effects of weightlessness and exposure to deep space radiation. The short-duration of these flight and the limits of medical technology of the era prevented a detailed understanding of the short-term effects of these exposures. Epidemiological analyses using the medical records for these individuals do not represent conclusive evidence as to the long-term cardiovascular health consequences. No data are available from the Apollo astronauts to ascertain any sex-specific effects. Some results from animal models are suggestive of combined effects of unloading and radiation exposure but the relative contributions have not been clearly defined, especially in the context of the mixed radiation exposure in deep space. It is currently unknown if spaceflight effects (e.g, weightlessness, reduced loading, circadian and immune dysregulation) and operations (e.g., altered oxygen levels [hyperoxia and hypoxia], sleep shifting) combined with radiation exposure will modify the cardiovascular disease risk.

Research approach: Combined exposures by hind-limb suspension and NSRL radiation and by radiation prior to flights on ISS in animals, and effects of duration (cell cultures, rodents). Occupational surveillance and data mining of medical records of future human subjects. Gateway human, cell and rodent studies will also be conducted.

Target for Closure

Understanding of the interaction between weightlessness and deep-space radiation on the cardiovascular system and to which degree duration plays a role, and whether it is relevant for later development of disease.

Identification and quantification of interactions of combined spaceflight factors on cardiovascular disease.
Identification of common pathways and mechanisms of damage and disease pathogenesis.

Mappings

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

Active

Defining the relationship between biomarkers of oxidative and inflammatory stress and atherosclerosis risk in astronauts during and after long-duration spaceflight (Lee)

Task Book: Entry
Principal Investigator: Lee, Stuart

Short Title: Cardio Ox (Cardiovascular Oxidative Damage)

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures (HHC) Element

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

SA 1. To determine the effects of long-duration spaceflight on measures of oxidative and inflammatory stress.

H1: Levels of inflammatory and oxidative biomarkers will be higher during long duration spaceflight, compared to pre-flight levels, and remain elevated immediately following spaceflight.

SA 2. To determine the effects of long-duration spaceflight on measures of arterial structure and function through R+3.

H1: Arterial function, assessed by flow-mediated dilation, will be impaired following long duration spaceflight through R+3. Carotid intima-medial thickness will increase in response to long duration spaceflight and will stay increased, although at a subclinical level, throughout recovery.

SA 3. To determine how alterations in vascular function and structure correlate with changes in circulating biomarkers of oxidative and inflammatory stress.

H1: Statistical analysis of these biomarkers and indices of atherosclerosis risk will yield a cadre of potential candidates for predictors of vascular dysfunction and atherosclerosis risk.

SA4: To monitor vascular status of astronauts for up to five years after the completion of their long-duration space flight mission (surveillance).

Resources (Flight)

Deliverables (2)

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

Description:
Quantify risk of vascular dysfunction and possible atherosclerosis risk

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

Category: Standard
Subcategory: Update

Description:
Quantify risk of vascular dysfunction and possible atherosclerosis risk

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

Combined Effects of Space Radiation and Microgravity on the Function of Human Capillaries and the Endothelial Barrier: Implications for Degenerative Disorders

Task Book: Entry
Principal Investigator: Grabham, Peter

Short Title: Implications for Degenerative Disorders

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Specific aim 1 endothelial barrier function.

To determine the permeability and tight junction integrity of experimental models

exposed to high and low LET space radiation in conjunction with microgravity.

Specific aim 2 Angiogenesis and mature vessel integrity.

To determine the additive or synergistic effect of microgravity on the effect of space

radiation on angiogenesis and on mature vessels.

Resources (None Listed)

Deliverables (1)

Defining the relationship between simulated weightlessness and space radiation on cardiovascular disease, and the effectiveness of a countermeasure

Task Book: Entry
Principal Investigator: Baker, John

Short Title: Microgravity and Radiation CVD Effects

Responsible HRP Element: Space Radiation

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Aim 1 will simulate a 6 month ISS human mission, determining the impact of simulated

weightlessness and space radiation [150 MeV protons (20 mGy), 1 GeV protons (20 mGy) and

600 MeV/n silicon (10 mGy)] on cardiac rhythm and risk for cardiac disease.

Specific Aim 2 will simulate a 3-3.5 year deep space human mission, determining the impact

of simulated weightlessness combined with components of galactic cosmic rays (60 % 1 GeV

protons, 20% 250 MeV/n helium, 10% 350 MeV/n oxygen and 10% 600 MeV/n silicon) with

total doses of 0.50 and 0.75 Gy plus appropriate controls on cardiac rhythm and risk for

cardiac disease.

Specific Aim 3 will determine the response to gamma radiation with and without simulated

weightlessness, to estimate relative biological effectiveness (RBE) for early clinically relevant

endpoints for cardiac rhythm and risk for cardiac disease. Rats will be irradiated with doses of

0.25, 0.5 Gy, 1.0 Gy and 2.0 Gy of 137Cs at Brookhaven National Laboratory alongside

experimental animals.

Resources (None Listed)

Deliverables (1)

Cardiovascular responses to simulated spaceflight: molecular signatures and surrogate outputs to measure CVD risk.

Task Book: Entry
Principal Investigator: Tahimic, Candice

Short Title: Cardiovascular responses to simulated spaceflight

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. Determine radiation dose-dependence of measures of cardiovascular performance in crew age-matched female and male mice in an acute ‘five-ion GCR simulation’ exposure model.

Aim 2. Determine effects of acute ‘five-ion GCR simulation’ exposure singly and in combination with simulated microgravity on cardiovascular performance measures in crew age-matched male and female mice, mimicking deep space missions.

Aim 3. Determine whether cardiovascular changes induced by GCR or in combination with HU correlate with specific and measurable behavioral, neuromotor and immune outcomes.

Resources (Other)

Deliverables (1)

Effect of Space Radiation on Innate Immune System Homeostasis Drives Immune and Endothelial Cell Dysfunction and Neurodegeneration

Task Book: Entry
Principal Investigator: O'Banion, Kerry

Short Title: Radiation Effects on Innate Immune System

Responsible HRP Element: Space Radiation

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Aim 1: Identify radiation-induced alterations in the bone marrow, focusing on myeloid cell inflammatory changes associated with aging and how these contribute to endothelial and immune system dysfunction as well as propensity for clonal hematopoiesis.
Aim 2: Identify similar effects in CNS myeloid cells (microglia) and their contribution to synaptic loss and cognitive dysfunction.
Aim 3: Identify potential intersection between systemic immune and CNS effects.

Resources (None Listed)

Deliverables (1)

Completed

Simulated Microgravity and Radiation-Induced Bone Degeneration: Oxidative Stress- and p53-Dependent Mechanisms

Task Book: Entry
Principal Investigator: Globus, Ruth

Short Title: 0g SR Bone

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:

To test the hypothesis that simulated weightlessness of mice modulates the response of bone and bone marrow to radiation, both acutely and during tissue regeneration.
To identify the target marrow-derived stem, progenitor and differentiated cell populations sensitive to the combined stimuli of simulated weightlessness and radiation.
To explore the relevance of specific ROS/RNS and p53-dependent mechanisms for mediating cellular responses to combined simulated weightlessness and radiation.

Resources (None Listed)

Deliverables (1)

Evaluation of the combined effects of gamma radiation and high dietary iron on oxidative damage and antioxidant status in rats

Task Book: Entry Unavailable
Principal Investigator: Zwart, Sarah

Short Title: Radiation/Iron

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Directed

Aims:
TBD

Integration/Unique Aspects: TBD

Resources (None Listed)

Deliverables (1)

Spaceflight effects on the mouse retina: Histological, gene expression and epigenetic changes after flight on STS-135

Task Book: Entry Unavailable
Principal Investigator: Zanello, Susana

Short Title: Spaceflight - Retina

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Directed

Aims:
This task will pursue the following aims: Specific Aim 1 will perform histological and gene expression analysis of retinas collected from C57BL/6 mice flown in STS-135 (and from their ground control counterparts) and compare these results to similar analyses performed on BALB mice from STS-133. Histological and gene expression outcomes will be focused on cellular stress, oxidative stress, DNA damage and cellular death and survival, but will also investigate genome-wide changes by expression microarray analysis. Specific Aim 2 will investigate whether retinal gene expression differences between STS135-flown mice and their gound counterparts may have an epigenetic basis, by analyzing DNA methylation in specific target genes. Using the same methodological approach. Specific Aim 3 plans to address a question related to the risk of circadian disruption. This aim will interrogate whether the expression of the non-visual photorreceptor "melanopsin", which is a major protein responsible for light-entrainment, remains intact during spaceflight (under the combined influence of space environmental factors as described above). Under this objective, we will compare the expression of melanopsin (Opsn4) in intrinsically photorreceptive retinal ganglion cells (ipRGC) in mouse retinas after spaceflight and in their ground controls, in both BALB (flight STS133) and CB57Bl/6 mice (flight STS135). Demonstrating that melanopsin expression remains unaffected by spaceflight is of high importance as additional evidence to support blue light as a countermeasure to prevent and mitigate circadian disruption in spaceflight crews.

Resources (None Listed)

Deliverables (1)

Combined effects of gamma radiation and high dietary iron on oxidative damage and antioxidant status in rat eyes

Task Book: Entry Unavailable
Principal Investigator: Zanello, Susana

Short Title: Iron-radiation-eye

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Directed

Aims:
Using a rat model, this task will pursue the following aims:

Specific Aim 1 will determine the individual and combined effects of gamma radiation and elevated iron on markers of oxidative damage and antioxidant status in various eye structures, namely, retina, cornea and lens.

Specific Aim 2 will investigate the relationship between the extent of oxidative stress damage and indexes of cellular functional status, namely apoptosis, inflammation and stress signaling pathways, measured by gene expression profiling and immunohistochemistry.

Resources (None Listed)

Deliverables (1)

Effects of high dietary heme iron and radiation on cardiovascular function (Radiation/Iron, CVD-Westby, Completed)

Task Book: Entry Unavailable
Principal Investigator: Westby, Chris

Short Title: Radiation/Iron, CVD

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures (HHC) Element

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Directed

Aims:

PART 1) HIGH DIETARY HEME IRON COMBINED WITH IRRADIATION PROMOTES A PROATHEROGENIC ENDOTHELIAL CELL PHENOTYPE DUE TO INCREASED OXIDATIVE STRESS

SPECIFIC AIMS

Aim 1: To determine the short-term consequences of the independent and combined effects of exposure to gamma radiation and elevated body iron stores on measures of endothelial function. We hypothesize that animals that have high body iron stores and are exposed to gamma radiation will show a greater reduction in endothelial dependent nitric oxide/cGMP production than animals that have only 1 of those treatments (either high iron stores or exposure to gamma radiation).

Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with endothelial cell barrier function. We hypothesize that modifications of genetic control and posttranslational expression of proteins associated with endothelial cell barrier function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment.

PART 2) OXIDATIVE MECHANISMS OF MYOCARDIAL TISSUE REMODELING IN A MODEL OF HIGH DIETARY HEME IRON EXPOSED TO RADIATION

Aim 1: To determine the short-term consequences of the independent and combined effects of gamma radiation and elevated body iron stores on measures of cardiac structure. We hypothesize that modifications to cardiac structure and function will be greater in rats with high body iron stores and exposed to gamma radiation than in rats that have only 1 of those treatments.

Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with cardiac structure and function. We hypothesize that modifications of genetic control and posttranslational expression of proteins associated with cardiac contractile function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment.

Resources (None Listed)

Deliverables (1)

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

Description:
The deliverable for this task will be a report (1. To determine the short-term consequences of the independent and combined effects of exposure to gamma radiation and elevated body iron stores on measures of endothelial function (2. Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with endothelial cell barrier function. (3. To determine the short-term consequences of the independent and combined effects of gamma radiation and elevated body iron stores on measures of cardiac structure. (4. Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with cardiac structure and function.
This task will contribute to the closure of N7.2 by determining which aspects of dietary intake, if any, significantly impact cardiovascular health during long duration spaceflight.

Internal Customers:
Human Health Countermeasures
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)

Improving CV Risk Prediction -- Biomarkers and Beyond, Implications for Astronaut Selection and Monitoring During Prolonged Spaceflight (CV BIOMARKERS / DE LEMOS / ACTIVE)

Task Book: Entry
Principal Investigator: de Lemos, James

Short Title: CV Biomarkers

Responsible HRP Element: Exploration Medical Capability

Collaborating Org(s):

National Space Biomedical Research Institute (NSBRI)

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Solicited

Aims:

Specific Aim 1: To establish a consortium of biomarker and aerospace medicine experts to provide

recommendations regarding biomarker screening in the astronaut population, and to conduct collaborative research focused on the specific risk prediction needs of the astronaut population.

Specific Aim 2: To develop a multi-modality risk prediction tool for 10 year global CVD events that combines imaging and novel blood-based biomarkers.

Specific Aim 3: To develop a risk prediction tool for short-term (3 year) global CVD events.

Exploratory Aim 4: To work with NASA researchers in the Human Research Program to explore the feasibility of transforming the Longitudinal Study of Astronaut Health (LSAH) into a prospective state-of-the art cohort study of the astronaut corps.

Resources (None Listed)

Deliverables (1)

Molecular mechanisms underlying heart failure and arrhythmias in astronauts (1-year NSBRI Postdoctoral Fellowship) (Molecular Arrhythmias-Gershovich/Werhans, Completed)

Task Book: Entry Unavailable
Principal Investigator: Gershovich, Pavel

Short Title: Molecular Arrhythmias

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

National Space Biomedical Research Institute (NSBRI)

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Solicited

Aims:

It has been documented that astronauts are susceptible to the development of cardiac arrhythmias and cardiomyopathy. Since we have identified a defect in cardiac ryanodine receptor (RyR2) associated with both arrhythmias and reduced cardiac contractility in patients with heart failure, we will investigate whether RyR2 dysfunction occurs as a result of external stressors associated with space travel.

In aim 1, we will determine the effects of hind limb suspension on cardiac electrophysiological parameters and arrhythmia susceptibility in mice. Moreover, changes in intracellular calcium release via RyR2 will be assessed in ventricular myocytes isolated from mice subjected to hind limb suspension.

In the second aim, we will determine the effects of protein radiation on the mouse heart. Electrophysiology studies will be performed during and following radiation to determine whether protein radiation provokes arrhythmogenesis. Finally, the effects of radiation will be determined on intracellular calcium release via RyR2.

Resources (None Listed)

Deliverables (1)

Determining the Effect of Space Flight on the Incidence of Cardiovascular Risk Factors and Disease (CV Data Mining-Barstow)

Task Book: Entry Unavailable
Principal Investigator: Barstow, Thomas

Short Title: CV Data Mining

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures (HHC) Element

Funding Status: Completed - Task completed and produced a deliverable

Procurement Mechanism(s):

Solicited

Aims:
Use data from the LSAH (Longitudinal Surveillance of Astronaut Health) and LSDA (Life Sciences Data Archive) to determine whether spaceflight induces a higher incidence of cardiovascular risk factors and disease in astronauts.

Resources (Other)

Deliverables (1)

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

Description:
Provide information to regarding the rate of cardiovascular disease found in astronauts:

1) Determine the rate of incidence of a “cardiovascular disease event” in astronauts
exposed to microgravity
2) Determine the rate of incidence of a “cardiovascular risk factor”, specifically blood
pressure and systemic inflammation (i.e C-reactive protein levels), in astronauts
3) Determine the rate of progression for cardiovascular disorders, specifically
atherosclerosis and hypertension in astronauts.
4) Evaluate the effects of mission duration and radiation exposure on the incidence of a
cardiovascular event, disorder, and risk factor
5) Provide a model that predicts the immediate and long-term risk of a “cardiovascular
disease event” in astronauts
6) Determine if an ECG arrhythmia during an extravehicular activity is a predictor of a
cardiovascular event later in life

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

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)

CVD Monitoring on Deep Space Gateway

Task Book: Entry Unavailable
Principal Investigator: TBD

Short Title: CVD Monitoring on DSG

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

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

Procurement Mechanism(s):

TBD

Aims:
To understand the interaction between weightlessness and deep-space radiation on the cardiovascular system and to which degree duration plays a role, and whether it is relevant for later development of disease. Identification and quantification of interactions of combined spaceflight factors on cardiovascular disease.

Resources (Flight)

Deliverables (1)