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All sourcesNASA NTRSDOE OSTI
NASA NTRS2024

Conclusions of a Mini Technical Interchange Meeting on New Cross Risk Integration Projects Managed by the NASA Space Radiation Element

To enable deep space exploration and sustained human presence in space, the NASA Human Research Program’s (HRP) Space Radiation Element (SRE) funds research to characterize and mitigate adverse health outcomes from exposure to space radiation that include risks of carcinogenesis, cardiovascular disease, and central nervous system decrements. Recently, the SRE was tasked with supporting multiple HRP Elements with innovative and enabling projects to inform risk characterization, facilitate mitigation activities, and support crew health and performance. These projects, such as precision health initiative, NASA Omics Archive (NOA) and human sample repositories, are agnostic to any HRP Element, hence the name, Cross-Risk Integration Projects (CRIP). CRIP serves 3 broad purposes: - Services: Generate samples and data and manage the receipt, inventory, archive, and ultimate redistribution of biospecimens created in HRP-funded spaceflight and analog research activities—includes NASA Omics Archive project and various human and animal sample repositories. - Method Development: Identify and evaluate new-to-NASA research or analysis methods or techniques that could fundamentally improve existing or planned research efforts—includes the Translational Radiation Research and Countermeasures Project. - Enabling Capabilities: Demonstrate real-world application by adapting, adopting, and/or developing capabilities to benefit crew health and performance and improve risk mitigation—includes Precision Health Initiative (Pharmacogenomics) and advanced biological systems and engineered tissue microsystems initiative (tissue chips, organ-on-a-chip). To identify new technologies, future work, and solicitations, the SRE organizes themed sessions at annual HRP Investigators’ Workshops (IWS). These technical interchange meetings (TIMs) provide a venue for the scientific community to present ongoing work and engage in open discussion of results, limitations of current approaches, and incorporation of novel experimental strategies, model systems, and other innovative techniques. Here, a summary of the studies presented at the SRE-sponsored mini-TIM at the HRP IWS along with the goals and objectives of the CRIP projects is communicated. The 90-min TIM had 6 speakers who presented impressive novel ideas and work, some of which are funded under CRIP by the Space Radiation Element.

Janapriya Saha↗
NASA NTRSDate not supplied

Countermeasures for Mitigation of Sensorimotor Decrements Following Head-Down Bed Rest

BACKGROUND Astronauts experience postflight disturbances in postural and locomotor control due to sensorimotor adaptations during spaceflight. These alterations may have adverse consequences if a rapid egress is required after landing. Although exercise is partially effective for mitigating cardiovascular and muscular deconditioning, additional countermeasures are needed to further preserve sensorimotor function for exploration missions. We have identified proprioceptive training and electrical muscle stimulation (EMS) as promising in-flight countermeasures. Since prolonged head down bed rest (HDBR) is a spaceflight analog for body unloading and causes postural and locomotor control decrements that parallel those observed after spaceflight, it can be used to accelerate the development of these countermeasures. METHODS This study will determine the effects of proprioceptive training and EMS on functional task performance and sensorimotor function following 60 days of 6° HDBR. Subjects will be randomly assigned to one of four groups: 1) an EMS arm, 2) a proprioceptive training arm, 3) an exercise plus proprioceptive training arm, and 4) a control arm. The EMS countermeasure will include daily bilateral stimulation of the quadriceps femoris muscle (30 minutes per session). Proprioceptive training will be performed three days per week (20 minutes per session) consisting of body-loaded postural tasks in the horizontal position on an air bearing sled. Exercise training will mimic current protocols used on the International Space Station, but treadmill aerobic exercise will be replaced with additional cycling aerobic exercise. Primary outcome measures will include pre and post HDBR functional tests that are representative of high priority exploration mission tasks and require high demand for dynamic control of postural stability. Additional measures will be used to identify the key physiological factors contributing to countermeasure benefits. Given the constrained samples size, a Bayesian modelling approach will be used to quantify the probability that there is an effect of a given magnitude. COUNTERMEASURE UPDATES Proprioceptive countermeasure design enhancements and human in the loop pilot testing continued through the Crew Health Countermeasures (CHC) Systems Capability Leadership Team (SCLT). The primary goals of this work were to enhance the visual feedback system’s capabilities and develop a proprioceptive training program for 60 days of HDBR. Six healthy non-astronaut volunteers participated in four pilot training sessions to systematically examine how each training variable (e.g., axial load, foot placement, and software profile) affects the overall proprioceptive challenge. The resulting training program will maintain an appropriate challenge during 60 days of HDBR by progressively decreasing the subject’s base of support, increasing tilt board target distances, and increasing axial loads using both subjective verbal feedback and objective performance data. RELEVANCE The deliverable from this project will be proof-of-concept sensorimotor countermeasure designs for functional task performance with full assessment of efficacy in a spaceflight analog. If the countermeasures are effective, they will be translated for validation with the suite of operationally implemented in-flight countermeasures.

T R Macaulay↗
NASA NTRSDate not supplied

Temporal Changes in Astronauts’ Muscle and Cardiorespiratory Physiology Before, During, and After Spaceflight

Background: NASA’s planned space exploration missions will require astronauts to safely perform extravehicular activity (EVA) and to safely egress vehicles in a variety of landing scenarios. Prolonged exposure to spaceflight can diminish tolerance for physical activity, decrease cardiovascular and sensorimotor function, cause loss of bone mineral density, as well as reduced muscle mass and strength. Although exercise can mitigate these spaceflight-induced physiological decrements, little is known regarding the time-course of changes in muscle and aerobic performance during spaceflight. Furthermore, these exercise countermeasures are not fully protective. For example, maximal aerobic capacity (VO2pk), lower body muscle cross-sectional area, and strength decrease by about 10% to 15% after short- (≈14 days) and long-duration (≈6 months) missions on the International Space Station (ISS). Future space missions longer in duration and further from Earth will employ exploration vehicles that will have exercise hardware with less robust and more constrained exercise capabilities than of those available on the ISS. Thus, countermeasures will need to be optimized to protect crew health and performance on exploration-class missions lasting up to 3 years. This requires a more detailed understanding of the dynamic effects of spaceflight on human health and performance, the ability of exercise to protect against this deconditioning, and the interaction of exercise with interrelated factors like nutrition, sleep, and environmental conditions. Methods: We will use standardized research and medical testing protocols previously validated in 1g and microgravity to quantify the time course and the inter-individual variability of changes in physical performance, including cardiorespiratory fitness and muscle strength and endurance, before, during, and after spaceflight missions lasting 2 months, 6 months, and 1 year. Additionally, we will use an extrapolation model to predict changes associated with multi-year exploration missions. Additionally, we will monitor in-flight exercise, nutrition, and sleep using in-flight assessment tools. Significance: Our testing protocols will provide valuable information for determining time course of change and the interindividual variability of spaceflight-induced deconditioning of aerobic capacity and muscle strength and endurance over the course of spaceflight missions up to and beyond 1 year. This information will be vital to assess whether humans can be physically ready for deep space exploration, such as on a mission to Mars, using current technology, or if additional mitigation strategies are necessary.

N Strock↗
NASA NTRSDate not supplied

Countermeasures for Mitigation of Sensorimotor Decrements Following Head-Down Bed Rest

BACKGROUND Astronauts experience postflight disturbances in postural and locomotor control due to sensorimotor adaptations during spaceflight. These alterations may have adverse consequences if a rapid egress is required after landing. Although exercise is partially effective for mitigating cardiovascular and muscular deconditioning, additional countermeasures are needed to further preserve sensorimotor function for exploration missions. We have identified proprioceptive training and electrical muscle stimulation (EMS) as promising in-flight countermeasures. Since prolonged head down bed rest (HDBR) is a spaceflight analog for body unloading and causes postural and locomotor control decrements that parallel those observed after spaceflight, it can be used to facilitate the development of these countermeasures. METHODS This study will determine the effects of proprioceptive training and EMS on functional task performance and sensorimotor function following 60 days of 6° HDBR. Subjects will be randomly assigned to one of four groups: 1)an EMS arm, 2) a proprioceptive training arm, 3) an exercise plus proprioceptive training arm, and 4) a control arm. The EMS countermeasure will include daily bilateral stimulation of selected bilateral lower extremity muscles (30 minutes per session). Proprioceptive training will be performed three days per week (20 minutes per session) consisting of body-loaded postural tasks in the horizontal position on an air bearing sled. Exercise training will mimic current protocols used on the International Space Station, but treadmill aerobic exercise will be replaced with additional cycling aerobic exercise. Primary outcome measures will include pre and post HDBR functional tests that are representative of high priority exploration mission tasks and require high demand for dynamic control of postural stability. Additional measures will be used to identify the key physiological factors contributing to countermeasure benefits. Given the constrained samples size, a Bayesian modelling approach will be used to quantify the probability that there is an effect of a given magnitude. HARDWARE AND PROTOCOL DEVELOPMENT Proprioceptive countermeasure design enhancements continued as part of the Mars Campaign Office (MCO) Crew Health and Performance (CHP) Crew Health Countermeasures (CHC). The primary goals of this work were to assemble a portable version of the countermeasure system that can be used at the :envihab facility, expand the software feedback system’s capabilities, and develop an actuator loading system that mimics what could be used on the International Space Station. In addition, one major piece of exercise hardware used in previous HDBR studies, the Horizontal Squat Device, was reassembled and restored to full functionality. Human-in-the-loop pilot testing is ongoing, prior to shipping both devices to the :envihab HDBR facility. Evaluations are also underway for the best EMS device technologies and specific methods. Finally, assessment techniques are being translated for administration in the horizontal position (e.g., leg dexterity and foot sole skin sensitivity). Our current goals are to refine the countermeasure training and assessment techniques and integrate protocols across multiple modalities. RELEVANCE The deliverable from this project will be proof-of-concept sensorimotor countermeasure designs for functional task performance with full assessment of efficacy in a spaceflight analog. If one or more countermeasures are effective, they will be translated for validation with the suite of operationally implemented in-flight countermeasures. ACKNOWLEDGEMENT This work is supported by NASA’s Human Research Program Human Health Countermeasures Element and by the Canadian Space Agency (L. Bent).

T R Macaulay↗
NASA NTRS2025

Countermeasures for Mitigation of Sensorimotor Decrements Following Head-Down Tilt Bed Rest

BACKGROUND Astronauts experience postflight disturbances in postural and locomotor control due to sensorimotor adaptations during spaceflight. These alterations may have adverse consequences if a rapid egress is required after landing. Although exercise is partially effective for mitigating cardiovascular and muscular deconditioning, additional countermeasures are needed to further preserve sensorimotor function. Proprioception training and electrical muscle stimulation (EMS) are two promising in-flight countermeasures. Since prolonged head down tilt bed rest (HDTBR) is a spaceflight analog for body unloading and causes postural and locomotor control decrements that parallel those observed after spaceflight, it can be used to facilitate the development of these countermeasures. METHODS This study will determine the effects of proprioception training and EMS on functional task performance and sensorimotor function following 60 days of 6° HDTBR. Subjects will be randomly assigned to one of four groups: 1) an EMS arm, 2) a proprioception training arm, 3) an exercise plus proprioceptive training arm, and 4) a control arm. The EMS countermeasure will include daily bilateral stimulation of selected bilateral lower extremity muscles (30 minutes per session). Proprioception training will be performed three days per week (25 minutes per session) consisting of body-loaded postural tasks in the horizontal position on an air bearing sled. Exercise training will mimic current protocols used on the International Space Station, but treadmill aerobic exercise will be replaced with additional cycling aerobic exercise. Primary outcome measures will include pre- and post- HDTBR functional tests that require high demand for dynamic control of postural stability. Secondary measures will be used to explore key physiological changes that underlie countermeasure benefits. All HDTBR and data collection activities will be completed by the German Aerospace Center (DLR) at the :envihab facility. Given the constrained samples size, a Bayesian modelling approach will be used to quantify the probability that there is an effect of a given magnitude. HARDWARE AND PROTOCOL DEVELOPMENT Final hardware modifications and protocol developments were completed in preparation for Campaign 1, which began in September 2024. These included shipment, setup, and operator training for the transportable gravity bed, horizontal squat device, foam obstacle course, EMS devices, leg dexterity system, foot sole skin sensitivity system, and Radiofrequency Echographic Multi Spectrometry (REMS) ultrasound device. In addition, specialized protocols were developed for data collection using DLR’s equipment, including muscle morphology magnetic resonance imaging (MRI), optical coherence tomography, venous blood flow MRI and ultrasound, muscle ultrasound and impedance, and skin blood flow ultrasound. We will present early data from the first campaign, which concluded in November, 2024. These will be compared with previous data from the recent 30-day HDTBR campaigns (Spaceflight associated neuro-ocular syndrome countermeasures (SANS-CM)) conducted at DLR. RELEVANCE The deliverable from this project will be proof-of-concept sensorimotor countermeasure designs for functional task performance with full assessment of efficacy in a spaceflight analog. If one or more countermeasures are effective, they will be translated for validation with the suite of operationally implemented in-flight countermeasures.

T R Macaulay↗
NASA NTRSDate not supplied

Temporal Changes in Astronauts’ Muscle and Cardiorespiratory Physiology Before, During and After Spaceflight

Background: NASA’s planned space exploration missions will require astronauts to safely perform extravehicular activity (EVA) and to safely egress vehicles in a variety of landing scenarios. Prolonged exposure to spaceflight can diminish tolerance for physical activity, decrease cardiovascular and sensorimotor function, and cause loss of bone mineral density, and reduced muscle mass and strength. Although exercise can mitigate these spaceflight-induced physiological decrements, little is known regarding the time-course of changes in muscle and aerobic performance during spaceflight. Furthermore, these exercise countermeasures are not fully protective. For example, maximal aerobic capacity (VO2pk), lower body muscle cross-sectional area, and strength decrease by about 10% to 15% after short- (~ 14 days) and long-duration (~ 6 months) missions on the International Space Station (ISS). Future space missions that are longer in duration and further from Earth will employ exploration vehicles that will have exercise hardware with less robust and more constrained exercise capabilities than of those available on the ISS. Thus, countermeasures will need to be optimized to protect crew health and performance on exploration-class missions that will last up to 3 years. This will require a more detailed understanding of the dynamic effects of spaceflight on human health and performance, and the ability of exercise to protect against this deconditioning, and the interaction of exercise with interrelated factors like nutrition, sleep, and environmental conditions. Methods: We will use standardized research and medical testing protocols previously validated in 1-G and 0-G to quantify the time course and the inter-individual variability of changes in physical performance, including cardiorespiratory fitness, and muscle strength, and endurance, before, during and after spaceflight missions lasting 2 months, 6 months, and 1 year. Additionally, we will use an extrapolation model to predict changes associated with 2–3-year exploration missions. Additionally, we will monitor in-flight exercise, nutrition, and sleep using in-flight assessment tools. Significance: Our testing protocols will provide valuable information for determining time course of change and the interindividual variability of spaceflight-induced deconditioning of aerobic capacity and muscle strength and endurance over the course of spaceflight missions up to and beyond 1 year. This information will be vital to assess whether humans can be physically ready for deep space exploration, such as on a mission to Mars, using current technology, or if additional mitigation strategies are necessary.

countermeasures↗
DOE OSTI2022

Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase

Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4-boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2009

Physiological Factors Contributing to Postflight Changes in Functional Performance

Astronauts experience alterations in multiple physiological systems due to exposure to the microgravity conditions of space flight. These physiological changes include sensorimotor disturbances, cardiovascular deconditioning and loss of muscle mass and strength. These changes might affect the ability of crewmembers to perform critical mission tasks immediately after landing on lunar and Martian surfaces. To date, changes in functional performance have not been systematically studied or correlated with physiological changes. To understand how changes in physiological function impact functional performance an interdisciplinary pre/postflight testing regimen (Functional Task Test, FTT) has been developed that systematically evaluates both astronaut postflight functional performance and related physiological changes. The overall objectives of the FTT are to: Develop a set of functional tasks that represent critical mission tasks for Constellation. Determine the ability to perform these tasks after flight. Identify the key physiological factors that contribute to functional decrements. Use this information to develop targeted countermeasures. The functional test battery was designed to address high priority tasks identified by the Constellation program as critical for mission success. The set of functional tests making up the FTT include the: 1) Seat Egress and Walk Test, 2) Ladder Climb Test, 3) Recovery from Fall/Stand Test, 4) Rock Translation Test, 5) Jump Down Test, 6) Torque Generation Test, and 7) Construction Activity Board Test. Corresponding physiological measures include assessments of postural and gait control, dynamic visual acuity, fine motor control, plasma volume, orthostatic intolerance, upper and lower body muscle strength, power, fatigue, control and neuromuscular drive. Crewmembers will perform both functional and physiological tests before and after short (Shuttle) and long-duration (ISS) space flight. Data will be collected on R+0 (Shuttle only), R+1, R+6 and R+30. Using a multivariate regression model we will identify which physiological systems contribute the most to impaired performance on each functional test. This will allow us to identify the physiological systems that play the largest role in decrement in functional performance. Using this information we can then design and implement countermeasures that specifically target the physiological systems most responsible for the altered functional performance associated with space flight.

Bloomberg, J. J.↗
DOE OSTI2025

Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity

Maternal obesity puts the offspring at high risk of developing obesity and cardiometabolic diseases in adulthood. Here, we utilized a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic perturbations seen in humans. We show increased adiposity in the offspring of HFD-fed mothers (Off-HFD) when compared with the offspring of regular diet-fed mothers (Off-RD). We have previously reported significant immune perturbations in the bone marrow of newly weaned Off-HFD. Here, we hypothesized that lipid metabolism is altered in the bone marrow of Off-HFD versus Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from 3-week-old Off-RD and Off-HFD. Diacylglycerols (DAGs), triacylglycerols (TAGs), sphingolipids, and phospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in Off-HFD, suggesting reduced delivery of cholesterol. These were accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from 3-wk-old mice and conducted metabolomic, lipidomic, and transcriptomic analyses. The lipidomic profiles of myeloid cells were similar to those of bone marrow cells and included increases in DAGs and decreased TAGs. Transcriptomics revealed altered expression of genes related to immune pathways, including macrophage alternative activation, B-cell receptors, and transforming growth factor-β signaling. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly weaned offspring of mothers with obesity, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.

RNA sequencing↗
NASA NTRS2011

Compression Stockings May Ameliorate Orthostatic Intolerance in Astronauts After Short-Duration Space Flight

Orthostatic intolerance following spaceflight has been observed since the early days of manned spaceflight, and no countermeasure has been 100% effective. During re-entry NASA astronauts currently wear an inflatable anti-gravity suit (AGS) which compresses the legs and abdomen, but this device is uncomfortable and loses effectiveness upon egress from the Space Shuttle. We previously reported that foot-to-thigh, gradient compression stockings were comfortable and effective during standing after Shuttle missions. More recently we showed in a ground-based model of spaceflight that the addition of splanchnic compression to the foot-to-thigh compression stockings, creating foot-to-breast high compression, improved orthostatic tolerance in hypovolemic subjects to a level similar to the AGS. Purpose: To evaluate a new three-piece, foot-to-breast high gradient compression garment as a countermeasure to post-spaceflight orthostatic intolerance. Methods: Fourteen astronauts completed this experiment (7 control, 7 treatment) following Space Shuttle missions lasting 12-16 days. Treatment subjects were custom-fitted for a three-piece, foot-to-breast high compression garment consisting of shorts and foot-to-thigh stockings. The garments were constructed to provide 55 mmHg compression at the ankle and decreased gradually to 15 mmHg over the abdomen. Orthostatic testing occurred ~30 days before flight (without garments) and ~2 hours after flight (with garments for treatment group only) on landing day. Blood pressure (BP) and heart rate (HR) were acquired for 2 minutes while the subject lay prone and then for 3.5 minutes after the subject stood. Data are reported as mean +/- SE. Results: The compression garment successfully prevented the tachycardia and hypotension typically seen post-spaceflight. On landing day, treatment subjects had a smaller change in HR (11+/-1 vs. 21+/-4 beats/min, p< or =0.05) and no decrease in systolic BP (2+/-4 vs. -9+/-2 mmHg, p< or =0.05). Garments also received good comfort ratings and were relatively easy to don. Conclusion: In this small group of astronauts, foot-to-breast high gradient compression garments seem to have prevented these negative effects of spaceflight on the cardiovascular responses to standing.

Platts, Steven H.↗
NASA NTRS2004

The Art of Space Flight Exercise Hardware: Design and Implementation

The design of space flight exercise hardware depends on experience with crew health maintenance in a microgravity environment, history in development of flight-quality exercise hardware, and a foundation for certifying proper project management and design methodology. Developed over the past 40 years, the expertise in designing exercise countermeasures hardware at the Johnson Space Center stems from these three aspects of design. The medical community has steadily pursued an understanding of physiological changes in humans in a weightless environment and methods of counteracting negative effects on the cardiovascular and musculoskeletal system. The effects of weightlessness extend to the pulmonary and neurovestibular system as well with conditions ranging from motion sickness to loss of bone density. Results have shown losses in water weight and muscle mass in antigravity muscle groups. With the support of university-based research groups and partner space agencies, NASA has identified exercise to be the primary countermeasure for long-duration space flight. The history of exercise hardware began during the Apollo Era and leads directly to the present hardware on the International Space Station. Under the classifications of aerobic and resistive exercise, there is a clear line of development from the early devices to the countermeasures hardware used today. In support of all engineering projects, the engineering directorate has created a structured framework for project management. Engineers have identified standards and "best practices" to promote efficient and elegant design of space exercise hardware. The quality of space exercise hardware depends on how well hardware requirements are justified by exercise performance guidelines and crew health indicators. When considering the microgravity environment of the device, designers must consider performance of hardware separately from the combined human-in-hardware system. Astronauts are the caretakers of the hardware while it is deployed and conduct all sanitization, calibration, and maintenance for the devices. Thus, hardware designs must account for these issues with a goal of minimizing crew time on orbit required to complete these tasks. In the future, humans will venture to Mars and exercise countermeasures will play a critical role in allowing us to continue in our spirit of exploration. NASA will benefit from further experimentation on Earth, through the International Space Station, and with advanced biomechanical models to quantify how each device counteracts specific symptoms of weightlessness. With the continued support of international space agencies and the academic research community, we will usher the next frontier in human space exploration.

Beyene, Nahom M.↗
NASA NTRS1993

Regulatory Mechanism of Muscle Disuse Atrophy in Adult Rats

During the last phase of NAG 2-386 we completed three studies. The effects of 14 days of weightlessness; the vastus medialis (VM) from flight rats in COSMOS 2044 was compared with the VM from tail suspended rats and other controls. The type I and II fibers in the mixed fiber portion of the VM were significantly reduced in flight rats and capillary densities paralleled the fiber density changes. The results of this project compared favorably with those in the extensor digitorum longus following seven days of flight in SL 3. The cardiovascular projects focused on the blood pressure changes in head down tilted rats (HDT) and non-head down tilted (N-HDT) rats. Blood pressures (MAP, SP and DP) were significantly elevated through seven days of HDT and rapidly returned to control levels within one day after removal from the HDT position. The N-HDT showed some slight rise in blood pressure but these were not as great and they were not as rapid. The HDT rats were characterized as exhibiting transient hypertension. These results led to some of the microvascular and vascular graduate student projects of Dr. Bernhard Stepke. Also our results refute or, at least, do not agree with previous reports from other laboratories. Each animal, in our blood pressure projects, served as its own control thereby providing more accurate results. Also, our experiments focused on recovery studies which can, in and of themselves, provide guidelines for flight experiments concerned with blood pressure changes. Another experiment was conducted to examine the role of testicular atrophy in whole body suspended (WBS) and tail suspended (TS) rats. We worked in conjunction with Dr. D.R. Deaver's laboratory at Pennsylvania State University and Dr. R. P. Amann at Colorado State University. In the TS rats the testes are retracted into the abdominal cavity, unless a ligature is placed to maintain them in the external scrotal sac. The cryptorchid condition in TS rats results in atrophy of the testes and lowered levels of spermatid formation. Hormonal changes due to testes atrophy must be considered in future experiments where related effects may modify muscle, bone or other tissue changes. Also, some new assessments of past results (published by many researchers) may warrant revised interpretations. The blood pressure studies and the testicular function results were presented and reviewed during an invited lecture at the University of Bordeaux II during the Animals in Space Symposium in March 1993. In summary, each of these three projects complied with the objectives of the proposal and serve to demonstrate the utility of animal models in preparations and interpretations of space flight results. All funding has been expended in accordance with the approved budget.

Source record↗
NASA NTRS2019

The Omics of Stem Cell Mediated Regeneration: A Pilot Single Cell RNA-Seq Study of Mechanotransduction

Mechanical forces are potent modulators of stem cell based tissue regenerative mechanisms, inducing cell fate decisions and tissue specific commitment. A unique platform for investigating mechanotransduction is spaceflight, where microgravity and altered fluid mechanics provide a loading-null experimental condition. Seminal investigations of regenerative capacity in a wholly regenerative species, the newt model, and in a variety of totipotent and adult stem cell populations have demonstrated the detrimental effects of unloading on maintenance of stem cell based regeneration. Of particular interest is the observation that unloading interferes with the transition of stem cell pools from proliferative state to differentiation commitment. In this work we sought to test the hypothesis that gravity mechanotransduction regulates stem cell tissue regenerative processes by modulating stem cell proliferation and differentiation fates at specific cell cycle stages. To do this, clonally-derived ESCs were plated on a collagen matrix and expanded for 36 hours before re-plating on a non-adherent culture dish in the absence of leukemia inhibitory factor (LIF) to form spheroid aggregate EBs. After formation, the EBs were transferred to a collagen matrix coated culture dishes and given 4 days to allow implantation and outgrowth. In parallel, totipotent ESCs were plated 24 hours before mechanical stimulation on collagen matrix culture dishes in the presence of LIF to maintain totipotency and serve as un-differentiation committed controls. The EBs and ESCs were then subjected to either a 60 minute pulse of gravity (static loading) or 60 minutes of cyclic stretch (dynamic loading) mechanotransduction. Six hours post-stimulation, we used a 10X Genomics Single Cell controller to generate bar-coded single cell Illumina libraries and sequenced expressomes for 5,000 static loaded cells, representative of a change in gravity mechanotransduction, 5,000 dynamic loaded cells, representative of tissue loading associate with physiologic function, and 5,000 unstimulated 1g control cells. The comparison of these 3 libraries by cluster assignment based on like gene expression patterns show substantial alteration in cluster geometry due to mechanical loading. Specifically the mechanically loaded EB outgrowth cells to retain potency markers (PAX6, SOX2, CD34) and suppress early commitment markers (Dhh, VCAN, Igf1). Whereas the EBs cultured under the non-stimulated conditions display clear departure from the ESC expressome with lineage commitment markers upregulated and several tissue specific markers being expressed (BMP "early musculoskeletal development, Mesp1" early cardiovascular cell lineage). These markers are not seen in the mechano-stimulated cultures or the totipotent ESC cultures. Comparison of like clusters between our experimental conditions revealed an array of regenerative and stem cell genes are significantly mechano-regulated. Of particular importance CDKN1a/p21, a gene shown by previous investigation of our research team to be significantly upregulated in unloading, was suppressed in the static and dynamic loaded EBS. In addition to CDKN1a/p21 many genes related to cell cycle and transitory differentiation markers had elevated expression in the mechano-stimulated EBs, but surprisingly these trends were not observed in the ESC cultures. This study is the first of its kind investigating for mechano-signaling and mechano-regulated pathways, and has alre

Single cell RNA-sequecing↗
DOE OSTI2022

Monte Carlo Simulation and Reconstruction: Assessment of Myocardial Perfusion Imaging of Tracer Dynamics With Cardiac Motion Due to Deformation and Respiration Using Gamma Camera With Continuous Acquisition

Purpose: Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) is routinely used for stress testing in nuclear medicine. Recently, our group extended its potential going from 3D visual qualitative image analysis to 4D spatiotemporal reconstruction of dynamically acquired data to capture the time variation of the radiotracer concentration and the estimated myocardial blood flow (MBF) and coronary flow reserve (CFR). However, the quality of reconstructed image is compromised due to cardiac deformation and respiration. The work presented here develops an algorithm that reconstructs the dynamic sequence of separate respiratory and cardiac phases and evaluates the algorithm with data simulated with a Monte Carlo simulation for the continuous image acquisition and processing with a slowly rotating SPECT camera. Methods: A clinically realistic Monte Carlo (MC) simulation is developed using the 4D Extended Cardiac Torso (XCAT) digital phantom with respiratory and cardiac motion to model continuous data acquisition of dynamic cardiac SPECT with slowly rotating gamma cameras by incorporating deformation and displacement of the myocardium due to cardiac and respiratory motion. We extended our previously developed 4D maximum-likelihood expectation-maximization (MLEM) reconstruction algorithm for a data set binned from a continuous list mode (LM) simulation with cardiac and respiratory information. Our spatiotemporal image reconstruction uses splines to explicitly model the temporal change of the tracer for each cardiac and respiratory gate that delineates the myocardial spatial position as the tracer washes in and out. Unlike in a fully list-mode data acquisition and reconstruction the accumulated photons are binned over a specific but very short time interval corresponding to each cardiac and respiratory gate. Reconstruction results are presented showing the dynamics of the tracer in the myocardium as it continuously deforms. These results are then compared with the conventional 4D spatiotemporal reconstruction method that models only the temporal changes of the tracer activity. Mean Stabilized Activity (MSA), signal to noise ratio (SNR) and Bias for the myocardium activities for three different target-to-background ratios (TBRs) are evaluated. Dynamic quantitative indices such as wash-in (K1) and wash-out (k2) rates at each gate were also estimated. Results: The MSA and SNR are higher with higher TBRs while biases were improved with higher TBRs to less than 10%. The correlation between exhalation-inhalation sequence with the ground truth during respiratory cycle was excellent. Our reconstruction method showed better resolved myocardial walls during diastole to systole as compared to the ungated 4D image. Estimated values of K1 and k2 were also consistent with the ground truth. Conclusion: The continuous image acquisition for dynamic scan using conventional two-head gamma cameras can provide valuable information for MPI. Our study demonstrated the viability of using a continuous image acquisition method on a widely used clinical two-head SPECT system. Our reconstruction method showed better resolved myocardial walls during diastole to systole as compared to the ungated 4D image. Precise implementation of reconstruction algorithms, better segmentation techniques by generating images of different tissue types and background activity would improve the feasibility of the method in real clinical environment.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1998

Uncoupling of the baroreflex by N(N)-cholinergic blockade in dissecting the components of cardiovascular regulation

Systemic administration of adrenergic agonists and nitric oxide donors is used extensively to determine cardiovascular receptor sensitivity. Conclusions regarding receptor sensitivity in the presence of the baroreflex may be misleading. In 8 normal volunteers, we determined the heart rate and blood pressure changes after incremental bolus doses of isoproterenol, phenylephrine, and sodium nitroprusside before and during neuronal nicotinic cholinergic (N(N)-cholinergic) blockade with trimethaphan. Results are given as median (25th/75th percentile). With trimethaphan, the baroreflex slope (as determined by bolus doses of nitroprusside and phenylephrine) decreased from 24 (22/26) to 0.00 (0.00/0.09) ms/mm Hg (P<0.01). The dose of isoproterenol that decreased systolic blood pressure (SBP) 12.5 mm Hg changed from 0.61 (0.51/5.3) to 0.17 (0.12/0.21) microg (P<0.01); the dose required to increase heart rate 12.5 bpm changed from 0.22 (0.17/0.41) to 0.74 (0.33/2.3) microg (P<0.01). The dose of nitroprusside required to decrease SBP 12.5 mm Hg changed from 2.3 (1.3/3.4) to 0.18 (0.14/0.24) microg/kg (P<0.01). The dose of phenylephrine required to increase SBP 12.5 mm Hg changed from 135 (110/200) to 16 (10/30) microg (P<0.01). We conclude that the efferent arc of the baroreflex can be completely interrupted with N(N)-cholinergic blockade. Estimation of adrenoreceptor sensitivity and sensitivity to nitric oxide donors by systemic administration of agonists is severely confounded by baroreflexes. Uncoupling of the baroreflex by N(N)-cholinergic blockade may be a useful method to obtain an integrated measure of adrenergic receptor sensitivity and sensitivity to nitric oxide donors in humans. This approach would permit the comparison of normal and abnormal physiological states without the "noise" of baroreflex buffering.

NASA Discipline Regulatory Physiology↗
NASA NTRS2003

Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels

BACKGROUND: Although abnormal L-arginine NO signaling contributes to endothelial dysfunction in the aging cardiovascular system, the biochemical mechanisms remain controversial. L-arginine, the NO synthase (NOS) precursor, is also a substrate for arginase. We tested the hypotheses that arginase reciprocally regulates NOS by modulating L-arginine bioavailability and that arginase is upregulated in aging vasculature, contributing to depressed endothelial function. METHODS AND RESULTS: Inhibition of arginase with (S)-(2-boronoethyl)-L-cysteine, HCl (BEC) produced vasodilation in aortic rings from young (Y) adult rats (maximum effect, 46.4+/-9.4% at 10(-5) mol/L, P<0.01). Similar vasorelaxation was elicited with the additional arginase inhibitors N-hydroxy-nor-L-arginine (nor-NOHA) and difluoromethylornithine (DFMO). This effect required intact endothelium and was prevented by 1H-oxadiazole quinoxalin-1-one (P<0.05 and P<0.001, respectively), a soluble guanylyl cyclase inhibitor. DFMO-elicited vasodilation was greater in old (O) compared with Y rat aortic rings (60+/-6% versus 39+/-6%, P<0.05). In addition, BEC restored depressed L-arginine (10(-4) mol/L)-dependent vasorelaxant responses in O rings to those of Y. Arginase activity and expression were increased in O rings, whereas NOS activity and cyclic GMP levels were decreased. BEC and DFMO suppressed arginase activity and restored NOS activity and cyclic GMP levels in O vessels to those of Y. CONCLUSIONS: These findings demonstrate that arginase modulates NOS activity, likely by regulating intracellular L-arginine availability. Arginase upregulation contributes to endothelial dysfunction of aging and may therefore be a therapeutic target.

Non-NASA Center↗