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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS1998

Interaction of Vascular Smooth Muscle Cells Under Low Shear Stress

The blood vessel wall consists of three cellular layers, an outer adventitial, a middle medial and an inner intimal layer. When the blood vessel forms in the embryo it begins as a tube composed of a single cell type called endothelial cells. Over time, other cells are recruited from the surrounding tissue to form additional layers on the outer surface of the endothelial tube. The cells that are recruited are called mesenchymal cells. Mesenchymal cells are responsible for the production of connective tissue that holds the blood vessel together and for developing into vascular smooth muscle cells that are responsible for regulating the diameter of the vessel (1) and therefore, blood flow. In a fully developed blood vessel, the endothelial cells make- up the majority of cells in the intimal layer while the mesenchymal cells make-up the majority of cells in the medial and adventitial layers. Within the medial layer of a mature vessel, cells are organized into multiple circular layers of alternating bands of connective tissue and cells. The cell layer is composed of a mixture of mesenchymal cells that have not developed into smooth muscle cells and fully developed smooth muscle cells (2). The assembly and organization of complex tissues is directed in part by a signaling system composed of proteins on the cell surface called adhesion molecules. Adhesion molecules enable cells to recognize each other as well as the composition of the connective tissue in which they reside (3). It was hypothesized that the different cell types that compose the vascular wall possess different adhesion molecules that enable them to recognize each other and through this recognition system, form the complex layered organization of the vascular wall. In other words, the layered organization is an intrinsic property of the cells. If this hypothesis is correct then the different cells that make up the vessel wall, when mixed together, should organize themselves into a layered structure resembling an intact blood vessel. Experiments described below were designed to test this hypothesis.

Seidel, Charles L.↗
NASA NTRS2001

Twisting integrin receptors increases endothelin-1 gene expression in endothelial cells

A magnetic twisting stimulator was developed based on the previously published technique of magnetic twisting cytometry. Using ligand-coated ferromagnetic microbeads, this device can apply mechanical stresses with varying amplitudes, duration, frequencies, and waveforms to specific cell surface receptors. Biochemical and biological responses of the cells to the mechanical stimulation can be assayed. Twisting integrin receptors with RGD (Arg-Gly-Asp)-containing peptide-coated beads increased endothelin-1 (ET-1) gene expression by >100%. In contrast, twisting scavenger receptors with acetylated low-density lipoprotein-coated beads or twisting HLA antigen with anti-HLA antibody-coated beads did not lead to alterations in ET-1 gene expression. In situ hybridization showed that the increase in ET-1 mRNA was localized in the cells that were stressed with the RGD-coated beads. Blocking stretch-activated ion channels with gadolinium, chelating Ca2+ with EGTA, or inhibiting tyrosine phosphorylation with genistein abolished twist-induced ET-1 mRNA elevation. Abolishing cytoskeletal tension with an inhibitor of the myosin ATPase, with an inhibitor of myosin light chain kinase, or with an actin microfilament disrupter blocked twisted-induced increases in ET-1 expression. Our results are consistent with the hypothesis that the molecular structural linkage of integrin-cytoskeleton is an important pathway for stress-induced ET-1 gene expression.

Non-NASA Center↗
NASA NTRS1996

Effect of Flow on Gene Regulation in Smooth Muscle Cells and Macromolecular Transport Across Endothelial Cell Monolayers

Endothelial cells line all of the vessels of the circulatory system, providing a non-thrombogenic conduit for blood flow; they regulate many complex functions in the vasculature, such as coagulation, fibrinolysis, platelet aggregation, vessel tone and growth, and leukocyte traffic; and they form the principal barrier to transport of substances between the blood and the surrounding tissue space. The permeability of endothelial cell changes with environmental stimuli; shear stress, in particular, applied either in vivo, or in vitro, induces changes in protein expression and secretion of vasoactive factors by endothelial cells. The ability to study the effects of shear on the macromolecular permeability of the cerebral vasculature is particularly important, since in no other place is the barrier function of the endothelium more important than in the brain. The endothelial cells of this organ have developed special barrier properties that keep the cerebral system from experiencing any drastic change in composition; together with glial cells, they form the blood brain barrier (BBB). We have studied the effect of flow on bovine BBB using flow chambers and tissue culture systems.

McIntire, Larry V.↗
NASA NTRS2005

By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

Parsons-Wingerter, Patricia↗
NASA NTRS2018

Space Radiation Induces Long Term Impact on the Cardiovascular System by the Activation of FYN Through Reactive Oxygen Species

Space radiation can damage the cardiovascular system and thus is an important health risk factor for astronauts during long-term space missions. We utilized publicly available transcriptomic data through NASA's GeneLab platform (genelab.nasa.gov) to determine cardiovascular system response to space radiation. GeneLab is an open repository that houses all NASA related omics experiments including on the International Space Station (ISS) and related radiation ground studies. We analyzed 3 datasets from GeneLab: GLDS-117 and GLDS-109, which are ground studies of cardiomyocytes followed-up for 28 days after exposure to 90cGy of proton at 1GeV and 15cGy of 56Fe at 1GeV; and GLDS-52, human endothelial cells (HUVECs) that were cultured for 10 days on the ISS. The ground studies were designed to characterize the long-term impact following space irradiation on cardiomyocytes for 5 different time points up to 28 days after irradiation. Our analysis was guided by the hypothesis that there are common persistent molecules affecting the cardiovascular system due to radiation effects during spaceflight. Endothelial cells are known to directly regulate the development and activity of cardiomyocytes, and thus their response to spaceflight should be highly correlated with cardiomyocytes. To investigate our hypothesis, we identified the molecular pathways that were modified for all time points compared across both radiation on the ground and the pathways found in HUVECs flown in the ISS. We found the following key results related to the cardiovascular systems: 1) space radiation downregulate ROS functions; and 2) the key/driving genes: FYN, LCK, AKT1 are upregulated and LYN and FOS are downregulated with FYN being the central driver/hub for the cardiovascular response to space radiation. It is worth noting the activation of FYN is a key event which prevents cardiac cell death and ROS production. From our study we thus hypothesize that a feedback loop occurs from the oxidative stress caused by space radiation that upregulates FYN which in turn reduces ROS levels and thus ROS pathways, preventing cardiomyocyte and endothelial cell death and thus protecting the cardiovascular systems. We believe that this is a novel mechanism for space radiation induced cardiovascular risk directly linking radiation ground studies to spaceflight

Beheshti, Afshin↗
NASA NTRS2004

Structural Evaluation of Radially Expandable Cardiovascular Stents Encased in a Polyurethane Film

A method of encasing cardiovascular stents with an expandable polyurethane coating has been developed to provide a smooth homogeneous inner wall allowing for a confluent growth of endothelial cells. In this design, the metal wire stent structure is completely covered by the polyurethane film minimizing biocorrosion of the metal (stainless steel or nitinol), and providing a homogeneous surface for surface treatment and incorporation of various eluting drugs to prevent platelet aggregation while supporting endothelialization. The polyurethane surface was treated with a helium plasma for sterilization and promotes growth of cells. The paper details the performance of the coated film to expand with the metal stent up to 225 % during deployment. We present stress/strain behavior of polyurethane films, and subsequent plasma treatment of the surface and the adhesion of the coating to the stent structure upon expansion. A film of less than 25 tm was found to be sufficient for corrosion resistance and flexibility without producing any excess stress on the stent structure. Straining the film to 225 % and plasma modification did not affect the mechanical and surface properties while allowing for improved biocompatibility as determined by the critical surface tension, surface chemistry, and roughness.

Trigwell, Steve↗
NASA NTRS2004

Molecular Basis of Mechano-Signal Transduction in Vascular Endothelial Cells

Simulated microgravity studies using a random positioning machine (RPM). One RPM machine has been built for us by Fokker Science in Netherland. Using the device, we have developed an in vitro system to examine the effect of simulated microgravity on osteoblastic bone cells. Using this system, we have carried out gene chip studies to determine the gene expression profiles of osteoblasts cultured under simulated microgravity conditions in comparison to static controls. From this study, we have identified numerous genes, some of which are expected ones inducing bone loss, but many of which are unexpected and unknown. These findings are being prepared for publications.

Jo, Hanjoong↗
NASA NTRS2012

Paramyxovirus Infection Mimics In Vivo Cellular Dynamics in Three-Demensional Human Bronchio-Epithelial Tissue-Like Assemblies

Respiratory syncytial virus and parainfluenza virus cause severe respiratory disease, especially in infants, children and the elderly. An in vitro model that accurately mimics infection of the human respiratory epithelium (HRE) would facilitate vaccine development greatly. Monolayer cultures traditionally used to study these viruses do not accurately and precisely differentiate the replication efficiencies of wild type and attenuated viruses. Therefore, we engineered novel three-dimensional (3D) tissue-like assemblies (TLAs) of human broncho-epithelial (HBE) cells to produce a more physiologically relevant in vitro model of the HRE. TLAs resemble HRE structurally and by expression of differentiated epithelial cell markers. Most significantly, wild type viruses exhibited a clear growth advantage over attenuated strains in TLAs unlike monolayer cultures. In addition, the TLAs responded to virus infection by secreting pro-inflammatory mediators similar to the respiratory epithelia of infected children. These characteristics make the TLA model a valuable platform technology to develop and evaluate live, attenuated respiratory virus vaccine candidates for human use. Respiratory virus diseases, the most frequent and least preventable of all infectious diseases, range in severity from the common cold to severe bronchiolitis and pneumonia . Two paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3), are responsible for a majority of the most severe respiratory diseases of infants and young children. RSV causes 70% of all bronchiolitis cases and is a major cause of morbidity and mortality worldwide, especially in infants. PIV3 causes 10-15% of bronchiolitis and pneumonia during infancy, second only to RSV, and 40% of croup in infants To date, licensed vaccines are not available to prevent these respiratory diseases. At present, traditional monkey kidney (Vero and LLC-MK2) and human (HEp-2) tissue culture cells and small animal models (mouse, cotton rat, guinea pig, ferret, and hamster) fail to accurately imitate viral replication and human disease states (8). Lacking an authentic model has impeded the development and evaluation of live, attenuated vaccine candidates. Development of a physiologically relevant in vitro tissue culture model that reproduces characteristics of the HRE, the primary target of RSV and PIV3, would aid in predicting clinical attenuation and safety of vaccine candidates. Successful tissue engineering of a 3D human intestinal model using novel NASA technology inspired the development of a tri-culture 3D model for the HRE. Sequential layering of primary mesenchymal cells (comprised of normal human fibroblasts and endothelial cells) followed by BEAS-2B epithelial cells derived from human bronchi and tracheae were recapitulated on Cultisphere and/or cytodex3 microcarriers in cylindrical vessels that rotate horizontally creating an organized epithelial structure. Horizontal rotation randomizes the gravity vector modeling aspects of microgravity. Mesenchymal and epithelial cells grown under these conditions reproduce the structural organization, multi-cellular complexity, and differentiation state of the HRE. The opportunity to study respiratory viruses in a nasal epithelium model is invaluable because the most promising respiratory virus vaccine candidates are live attenuated viruses for intranasal administration. Here we characterize the interactions of respiratory viruses and epithelial cells grown under modeled microgravity in comparison to gravity-ladened monolayers. 3D HBE TLAs and traditional monolayers (2D) are infected at 35 C, the upper temperature of the upper HRE, to simulate in vivo infection conditions. Growth kinetics of wild type (wt) RSV and PIV3 viruses were compared in 2D and 3D cells to that of strains attenuated in humans or rhesus macaques. This novel 3D HBE model also offers an opportunity to study whether the epithelial cell function, especially in host defenses recapitulated by mimicking the structural organization of the HRE. In vivo, airway epithelial cells play a significant and dynamic role in host defense by blocking paracellular permeability and modulating airway function through cellular interactions or tight junctions. As regulators of the innate immune response, epithelial cells constitutively express cytokines, chemokines, and colony stimulating factors including RANTES, IL-8, IL-6, GM-CSF, and G-CSF for proactive host defense. In response to viral infection, epithelial cells induce potent immuno-modulatory and pro-inflammatory cytokines that recruit phagocytic and inflammatory cells to clear the virus and enhance protection. Although disease pathogenesis is classically attributed to the cytopathic effects of the pathogen, severe disease states associated with RSV and PIV3 are attributed to the inflammatory response, especially in infants. RSV is a potent inducer of cytokines and pro-inflammatory mediators in epithelial cells in vivo. A differentiated human epithelial model independent of the complete functional immune system will help elucidate the role of epithelial cells in respiratory disease. We reported here, virus and host cell interactions in 3D HBE TLAs are similar to that in vivo. Because the epithelial cell organization of the TLAs impacts not only the expression of airway epithelial characteristics, but also cellular communication, the TLAs represent a more physiologically relevant model of the HRE than BEAS-2B or other non-tumour monolayer models of respiratory disease. As a result, wild type respiratory viruses have a clear growth advantage over attenuated viruses in TLAs unlike traditional monolayers. In addition, the TLAs respond to wild type virus infection by secreting pro-inflammatory mediators characteristic of infected HRE. TLAs expressing microbial defense mechanisms provide an excellent model to study the interactions of respiratory pathogens with their host and to identify the innate immunity mediators. Therefore, 3D HBE TLAs offer advantages for the study of respiratory viruses and the development of viral vaccine candidates.

Deatly, Anne M.↗
NASA NTRS1988

Shear stress induced stimulation of mammalian cell metabolism

A flow apparatus was developed for the study of the metabolic response of anchorage dependent cells to a wide range of steady and pulsatile shear stresses under well controlled conditions. Human umbilical vein endothelial cell monolayers were subjected to steady shear stresses of up to 24 dynes/sq cm, and the production of prostacyclin was determined. The onset of flow led to a burst in prostacyclin production which decayed to a long term steady state rate (SSR). The SSR of cells exposed to flow was greater than the basal release level, and increased linearly with increasing shear stress. It is demonstrated that shear stresses in certain ranges may not be detrimental to mammalian cell metabolism. In fact, throughout the range of shear stresses studied, metabolite production is maximized by maximizing shear stress.

Mcintire, L. V.↗
NASA NTRSDate not supplied

Developing High-Throughput Organ-on-a-Chip Models to Investigate the Effects of Ionizing Radiation on the Central Nervous System

One of the main health risks in human space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to the galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neuronal damage and neuroinflammation associated with cognitive and behavioral dysfunction. In general, the extent of CNS damage is partially regulated by the blood-brain barrier (BBB), which enables immune cells to enter the CNS. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, immune responses and oxidative stress, and thus could serve as a robust CNS-specific target for countermeasure development. However, studies on BBB permeability and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we established a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments in response to ionizing radiation, based on commercially available OrganoPlates (Mimetas, Inc.) seeded with primary or induced pluripotent stem cell-derived human cells. We investigated both immediate and delayed CNS responses to major GCR components: 0.15-0.5 Gy 250MeV/n 4-He, and 0.3-0.8 Gy 600 MeV/n 56-Fe; as well as to 0.5-1 Gy X-rays. We observed ionizing radiation-mediated increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by morphological changes in endothelial cells and tight junctions, altered cytokine profile including TNFa upregulation, and increased oxidative stress. We also quantified irradiation-mediated changes in astrocyte activation and neuronal functions, revealing major astrocyte damage mediated by 600MeV/n 56-Fe particles. Thus, we demonstrate that deep space radiation may contribute to CNS damage by disrupting both astrocyte and endothelial cell components of the blood-brain barrier. Our next steps include mapping and validating the transcriptomic changes induced by simulated GCRs and their components in human CNS models. Ultimately, we aim to uncover potential novel targets for countermeasure developments to mitigate CNS damage in long duration spaceflight.

Radiation↗
NASA NTRS1992

Extracellular matrix as a solid-state regulator in angiogenesis: identification of new targets for anti-cancer therapy

Angiogenesis, the growth of blood capillaries, is regulated by soluble growth factors and insoluble extracellular matrix (ECM) molecules. Soluble angiogenic mitogens act over large distances to initiate capillary growth whereas changes in ECM govern whether individual cells will grow, differentiate, or involute in response to these stimuli in the local tissue microenvironment. Analysis of this local control mechanism has revealed that ECM molecules switch capillary endothelial cells between differentiation and growth by both binding specific transmembrane integrin receptors and physically resisting cell-generated mechanical loads that are applied to these receptors. Control of capillary endothelial cell form and function therefore may be exerted by altering the mechanical properties of the ECM as well as its chemical composition. Understanding of this mechanochemical control mechanism has led to the development of new angiogenesis inhibitors that may be useful for the treatment of cancer.

Review↗
NASA NTRS2017

Vascular Patterning Analysis by VESGEN 2D/3D with Bioinformatics: Updates for Rodent Tissues

Fractally branching vascular systems are a complex physiological requirement shared by humans with all higher terrestrial life forms, including other vertebrates, insects, and higher land plants. Vascular trees, networks, and tree-network composites are therefore mapped and quantified by the VESsel GENeration Analysis (VESGEN) software according to weighted physiological vascular rules that include vessel connectivity, tapering and bifurcational branching. According to fluid dynamics, successful vascular transport depends upon a complex distributed system of highly regulated laminar flow. VESGEN has elucidated changes in vascular patterning resulting from inflammatory, developmental and other signaling pathways within numerous tissues of major model organisms important for Space Biology, especially for rodents. Important early stage regenerative opportunities have been identified by VESGEN vascular analysis for visual impairments in the human retina, and is currently being used for research into astronaut visual and ocular disorders associated with long duration missions. The VESGEN 2D software is a mature, automated, widely published capability for which beta testing and public release by NASA is planned for the upcoming year. Early-stage capabilities for VESGEN 3D analysis are under development for the rodent retina and intestine as prototype tissues. A prototype VESGEN 2D Bioinformatics software capability has also been developed to associate phenotypic changes in molecular expression with vascular structure and function. By new VESGEN bioinformatic innovations, expression patterns of the genetic, transcriptional, protein and other markers for regulatory molecules such as vascular endothelial growth factor (VEGF) and their receptors, often indicators of tissue oxygenation status, are co-localized with alterations in vascular pattern. Biomarkers are therefore mapped and quantified as information dimensions directly correlated with the spatial dimensions of a vascular pattern. Further important technology innovations by NASA include substantial image segmentation advances for more automated binary extraction of the grayscale vascular patterns, together with informative associated image quality assessments. Vascular mapping and quantification capabilities for the rodent retina and intestine are illustrated for VESGEN 2D, along with technology status reports on VESGEN 3D and Bioinformatic capabilities. Research partially supported by Ames Center Innovation Awards.

Parsons-Wingerter, P.↗
NASA NTRSDate not supplied

Neurovascular Outcomes of Space Radiation in Human Blood-Brain Barrier Models

One of the main health risks in human deep space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neurodegeneration and neuroinflammation associated with cognitive and behavioral dysfunction. The extent of CNS damage is partially mediated by the blood-brain barrier (BBB), which regulates the interaction between CNS and systemic responses to stressors in the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, neuroinflammation and oxidative stress. However, studies on BBB and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we developed a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments caused by deep space radiation. We investigated both immediate and delayed CNS responses to major GCR components: 0.15-0.5Gy 250MeV/n 4He and 0.3-0.8Gy 600MeV/n 56Fe; as well as to 0.5-1Gy X-rays. We observed ionizing radiation-mediated increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by damage to endothelial cells and tight junctions, altered cytokine expression including TNFalpha upregulation, and increased oxidative stress. In particular, 600MeV/n 56Fe particle irradiation selectively induced astrocyte damage and increased blood-brain barrier permeability only in models that contained astrocytes in addition to endothelial cells, indicating astrocytes as a particularly radiosensitive component of the CNS that could therefore be a suitable a target for neuroprotection. Future studies will compare human and mouse CNS model responses to simulated GCRs and evaluate the induction of an anti-inflammatory phenotype in astrocytes as a potential countermeasure. Ultimately, we aim to expand upon these results to uncover novel cellular and mechanistic targets for countermeasure development to mitigate human CNS damage in deep space exploration.

centrat nervous system↗
NASA NTRSDate not supplied

Neurovascular Outcomes of Ionizing Radiation in Human Blood-Brain Barrier Models

One of the main health risks in human deep space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neurodegeneration and neuroinflammation associated with cognitive and behavioral dysfunction. The extent of CNS damage is partially mediated by the blood-brain barrier (BBB), which regulates the interaction between CNS and systemic responses to stressors in the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, neuroinflammation and oxidative stress. However, studies on BBB and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we developed a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments caused by deep space radiation. We investigated both immediate and delayed CNS responses to major GCR components: 0.15-0.5Gy 250MeV/n 4He and 0.3-0.8Gy 600MeV/n 56Fe; as well as to 0.5-1Gy X-rays. We observed ionizing radiation-mediated increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by damage to endothelial cells and tight junctions, altered cytokine expression including TNFalpha upregulation, and increased oxidative stress. In particular, 600MeV/n 56Fe particle irradiation selectively induced astrocyte damage and blood-brain barrier permeability only in models that contained astrocytes in addition to endothelial cells, indicating astrocytes as a particularly radiosensitive component of the CNS that could therefore be a suitable a target for neuroprotection. Future studies will compare human and mouse CNS model responses to simulated GCRs and evaluate the induction of an anti-inflammatory phenotype in astrocytes as a potential countermeasure. Ultimately, we aim to expand upon these results to uncover novel cellular and mechanistic targets for countermeasure development to mitigate human CNS damage in deep space exploration.

space radiation↗
NASA NTRSDate not supplied

Neuroimmune responses to space radiation

One of the main health risks in human deep space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neurodegeneration and neuroinflammation associated with cognitive and behavioral dysfunction. The extent of CNS damage is partially mediated by the blood-brain barrier (BBB), which regulates the interaction between CNS and systemic responses to stressors in the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, neuroinflammation and oxidative stress. However, studies on BBB and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we developed a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments caused by deep space radiation. We investigated both immediate and delayed CNS responses to major GCR components: 0.3-0.8Gy 600MeV/n 56Fe ions; as well as to 0.5-1Gy X-rays. We observed ionizing radiation-mediated increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by damage to endothelial cells and tight junctions, altered cytokine expression including TNFalpha upregulation, and increased oxidative stress. In particular, 600MeV/n 56Fe particle irradiation selectively induced astrocyte damage and increased blood-brain barrier permeability only in models that contained astrocytes in addition to endothelial cells, indicating astrocytes as a particularly radiosensitive component of the CNS that could therefore be a suitable a target for neuroprotection. Future studies will compare human and mouse CNS model responses to simulated GCRs and evaluate the induction of an anti-inflammatory phenotype in astrocytes as a potential countermeasure. Furthermore, in our lab we have been exploring the individual variability, genomic associations and secreted biomarkers of responses to space radiation, which could eventually be combined to address personalized CNS health risk and develop individual countermeasures. Ultimately, we aim to expand upon these results to uncover novel cellular and mechanistic targets for countermeasure development to mitigate human CNS damage in deep space exploration.

space radiation↗
NASA NTRSDate not supplied

B Complex 5-Methyltetrahydrofolate, Riboflavin, Pyridoxine, and Methylcobalamin Supplementation as a Non-Mechanical Countermeasure to Mitigate Optic Disc Edema Changes During Strict 6º Head-Down Tilt Bed Rest

A subset of astronauts on International Space Station missions have experienced optic disc edema, part of what is characterized as Spaceflight Associated Neuro-ocular Syndrome (SANS). While the precise cause of SANS is unknown, it is likely that there are multiple contributing factors, including genetic and environmental factors. Our recent work has shown that crewmembers with SANS have higher concentrations of metabolic biomarkers of impairments in the one-carbon metabolic pathway compared to unaffected astronauts - before, during, and after f light (1). B-vitamin status and the presence of one-carbon pathway single nucleotide polymorphism (SNP) variants predicted the incidence of SANS pathologies, including optic disc edema (2). Specifically, the G allele of methionine synthase reductase (MTRR) A66G and the C allele of serine hydroxymethyltransferase-1 (SHMT1) C1420T were associated with increased incidence of SANS pathologies (2). In a recent 30-d bed rest head-down tilt study with 0.5% CO2 exposure, 5 of 11 subjects developed optic disc edema (4) and the same SHMT1 C1420T and MTRR A66G genetic variants were associated with a larger increase in total retina thickness, a quantitative measure of optic disc edema (5). We published a multi-hit hypothesis of how genetics represents an indispensable element of SANS, which is a multifactorial problem (6). In brief: endothelial dysfunction secondary to genetic, biochemical/nutritional, and physiological (e.g., cardiovascular/fluid shift) f actors could lead to optic disc edema and the other ocular changes that occur in SANS. We expanded this hypothesis to include the possibility that genetic effects on B-vitamin status can alter nitric oxide synthesis and oxidative stress in the endothelium. This in turn could alter the turnover of structural components of the sclera, making it more susceptible to pathologic changes when faced with stressors related to the unrelenting headward fluid shift that occurs in weightlessness and strict head-down tilt bed rest (5). If the relationships that we have observed in flight and ground-based research hold true for the SANS Countermeasure Study, these genetic factors could predict who will be more susceptible to the development of SANS, and more importantly could also provide countermeasure options. As has been shown extensively in the literature, vitamin supplementation can serve to overcome genetic hindrances to one-carbon biochemistry and vascular physiology. Thus, based on our findings, publications, and hypotheses, supported by extensive supporting literature, we had hoped to test in the SANS Countermeasure Study the efficacy of a bioactive B-vitamin complex as a countermeasure to optimize function of the one-carbon pathway and prevent or mitigate optic disc edema during strict 6-degree head down tilt bed rest, and ultimately in space f light. While the supplement is no longer planned to be tested in the SANS Countermeasure Study because of laws regulating supplementation studies like this costing much more than initially planned, we will assess the contribution of one-carbon pathway genetics and B-vitamin status to SANS risk.

S R Zwart↗
NASA NTRSDate not supplied

Development of A Directed Acyclic Graph for Venous Thromboembolism During Spaceflight

Introduction: Recent studies have reported the development of venous blood flow stasis in astronauts and an occlusive venous thrombosis during spaceflight. Subsequent investigations revealed approximately one quarter of surveilled crew members had some degree of blood flow stasis in the left internal jugular vein. Therefore, NASA’s Human System Risk Board now formally tracks venous thromboembolism (VTE) as a “concern” for human spaceflight. To investigate potential mechanisms by which exposures concomitant with spaceflight (e.g., microgravity, radiation) may contribute to VTE, we developed a causal diagram in the form of a directed acyclic graph (DAG). Methods: The mechanisms by which spaceflight exposures may elevate the risk of VTE and the downstream effects on mission outcomes were critically analyzed, taking into account scientific literature and subject matter expertise consultation, and a DAG was generated. A Level-of-Evidence score for each causal relationship was assigned based on assessing the literature against a set of criteria derived from the A. Bradford Hill Causal Guidelines. Results: The set of three main factors that predispose people to VTE (hypercoagulability, endothelial damage, and blood stasis) is known as Virchow’s Triad. In constructing the DAG for VTE we articulated various mechanisms by which the principal spaceflight hazards (microgravity, radiation, closed hostile environment, isolation and confinement, distance from Earth) are thought to interact with or cause the components in Virchow’s triad. We found sufficient evidence to at least speculate that fluid shifts from microgravity, compensatory alterations in hematologic indices, spaceflight atmospheric conditions, and oxidative stress/inflammation from radiation may be potential contributors to VTE development. Discussion: Developing the DAG entailed a systematic and repeatable approach for visualizing relationships between contributing factors that may lead to VTE in spaceflight. Articulating pathways linking spaceflight exposures to VTE risk factors and possible VTE development enables subject matter experts from different domains to construct a shared mental model. Assignment of levels of evidence scores to the relationships helps identify knowledge and capability gaps that should be considered for further investigation. Furthermore, the DAG highlights modifiable variables and may therefore facilitate the development of new VTE risk mitigation strategies.

Alexander Svoronos↗
NASA NTRSDate not supplied

Neuroimmune Responses to Space Radiation

One of the main health risks in human deep space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neurodegeneration and neuroinflammation associated with cognitive and behavioral dysfunction. The extent of CNS damage is partially mediated by the blood-brain barrier (BBB), which regulates the interaction between CNS and systemic responses to stressors in the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, neuroinflammation and oxidative stress. However, studies on BBB and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we developed a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments caused by deep space radiation. We investigated both immediate and delayed CNS responses to major GCR components: 600MeV/n 56Fe ions. We observed ionizing radiation-mediated dose-dependent increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by altered cytokine expression including interleukin-1 receptor alpha downregulation, and increased oxidative stress. In particular, 600MeV/n 56Fe particle irradiation selectively increased damage and blood-brain barrier permeability only in models that contained astrocytes in addition to endothelial cells, indicating astrocytes as a particularly radiosensitive component of the CNS that could therefore be a suitable a target for neuroprotection. Future studies will compare human and mouse CNS model responses to simulated GCRs and evaluate the induction of an anti-inflammatory phenotype in astrocytes as a potential countermeasure. Furthermore, in our lab we have been exploring the individual variability, genomic associations and secreted biomarkers of responses to space radiation, which could eventually be combined to address personalized CNS health risk and develop individual countermeasures. Ultimately, we aim to expand upon these results to uncover novel cellular and mechanistic targets for countermeasure development to mitigate human CNS damage in deep space exploration.

space radiation↗