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NASA NTRS2004

Transgenic plants with increased calcium stores

The present invention provides transgenic plants over-expressing a transgene encoding a calcium-binding protein or peptide (CaBP). Preferably, the CaBP is a calcium storage protein and over-expression thereof does not have undue adverse effects on calcium homeostasis or biochemical pathways that are regulated by calcium. In preferred embodiments, the CaBP is calreticulin (CRT) or calsequestrin. In more preferred embodiments, the CaBP is the C-domain of CRT, a fragment of the C-domain, or multimers of the foregoing. In other preferred embodiments, the CaBP is localized to the endoplasmic reticulum by operatively associating the transgene encoding the CaBP with an endoplasmic reticulum localization peptide. Alternatively, the CaBP is targeted to any other sub-cellular compartment that permits the calcium to be stored in a form that is biologically available to the plant. Also provided are methods of producing plants with desirable phenotypic traits by transformation of the plant with a transgene encoding a CaBP. Such phenotypic traits include increased calcium storage, enhanced resistance to calcium-limiting conditions, enhanced growth and viability, increased disease and stress resistance, enhanced flower and fruit production, reduced senescence, and a decreased need for fertilizer production. Further provided are plants with enhanced nutritional value as human food or animal feed.

Wyatt, Sarah↗
NASA NTRS2005

The Evaluation of Methicillin Resistance in Staphylococcus aboard the International Space Station

The International Space Station (ISS) represents a semi-closed environment with a high level of crewmember interaction. As community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a health concern in environments with susceptible hosts in close proximity, an evaluation of isolates of clinical and environmental Staphylococcus aureus and coagulase negative Staphylococcus was performed to determine if this trend was also present in astronauts aboard ISS or the space station itself. Rep-PCR fingerprinting analysis of archived ISS isolates confirmed our earlier studies indicating a transfer of S. aureus between crewmembers. In addition, this fingerprinting also indicated a transfer between crewmembers and their environment. While a variety of S. aureus were identified from both the crewmembers and the environment, phenotypic evaluations indicated minimal methicillin resistance. However, positive results for the Penicillin Binding Protein, indicative of the presence of the mecA gene, were detected in multiple isolates of archived Staphylococcus epidermidis and Staphylococcus haemolyticus. Phenotypic analysis of these isolates confirmed their resistance to methicillin. While MRSA has not been isolated aboard ISS, the potential exists for the transfer of the gene, mecA, from coagulase negative environmental Staphylococcus to S. aureus creating MRSA strains. This study suggests the need to expand environmental monitoring aboard long duration exploration spacecraft to include antibiotic resistance profiling.

Ott, C. M.↗
NASA NTRS2009

Cell Cycle Progression of Human Cells Cultured in Rotating Bioreactor

Space flight has been shown to alter the astronauts immune systems. Because immune performance is complex and reflects the influence of multiple organ systems within the host, scientists sought to understand the potential impact of microgravity alone on the cellular mechanisms critical to immunity. Lymphocytes and their differentiated immature form, lymphoblasts, play an important and integral role in the body's defense system. T cells, one of the three major types of lymphocytes, play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors. Reported studies have shown that spaceflight can affect the expression of cell surface markers. Cell surface markers play an important role in the ability of cells to interact and to pass signals between different cells of the same phenotype and cells of different phenotypes. Recent evidence suggests that cell-cycle regulators are essential for T-cell function. To trigger an effective immune response, lymphocytes must proliferate. The objective of this project is to investigate the changes in growth of human cells cultured in rotating bioreactors and to measure the growth rate and the cell cycle distribution for different human cell types. Human lymphocytes and lymphoblasts will be cultured in a bioreactor to simulate aspects of microgravity. The bioreactor is a cylindrical culture vessel that incorporates the aspects of clinostatic rotation of a solid fluid body around a horizontal axis at a constant speed, and compensates gravity by rotation and places cells within the fluid body into a sustained free-fall. Cell cycle progression and cell proliferation of the lymphocytes will be measured for a number of days. In addition, RNA from the cells will be isolated for expression of genes related in cell cycle regulations.

Parks, Kelsey↗
NASA NTRS2010

CHOICE - Directed Study: Consequences of longterm- Confinement and Hypobaric HypOxia on Immunity in the Antarctic Concordia Environment

Concerning ground-based space physiological research, the choice of analog must carefully match the system of interest. For spaceflight-associated immune dysregulation (SAID), Antarctica winter-over has emerged as potentially the best terrestrial analog. The prolonged mission durations, extreme/dangerous environment, station-based lifestyle, isolation from outside world, disrupted circadian rhythms, and other psychological aspects make this analog extremely high fidelity for exploration-class space missions (long duration lunar, Mars). NASA, ESA and RSA are currently investigating SAID, with NASA currently operating the Integrated Immune flight study. It is desirable to have a ground analog for SAID validated, so that potential countermeasures might be validated terrestrially prior to during flight. For this presentation, NASA data collected on the winterover 2009 crewmembers, baseline through early deployment will be presented. Through early deployment (approximately 2-3 weeks at Concordia), phenotypic alterations included increased levels of memory T cells, shifts among the CD8+ T cell compartment to a more mature phenotype, and increases in constitutively activated T cells. CD8+/IFNg+ T cell percentages, and T cell blastogenesis functional responses were depressed early deployment as compared to healthy controls. In four compatible subjects, secreted T cell Th1/Th2 cytokines were measured following culture stimulation, and a Th2 shift was observed as compared to controls. Post-winter over frozen sample return will be required to determine if this shift persisted during the winter over period. Additionally, circadian rhythms remained altered compared to baseline, as determined through 5x daily cortisol measurements. Latent viral reactivation will not be determined until frozen sample return occurs.

Sams, Clarence↗
NASA NTRS2010

Shorebird Migration Patterns in Response to Climate Change: A Modeling Approach

The availability of satellite remote sensing observations at multiple spatial and temporal scales, coupled with advances in climate modeling and information technologies offer new opportunities for the application of mechanistic models to predict how continental scale bird migration patterns may change in response to environmental change. In earlier studies, we explored the phenotypic plasticity of a migratory population of Pectoral sandpipers by simulating the movement patterns of an ensemble of 10,000 individual birds in response to changes in stopover locations as an indicator of the impacts of wetland loss and inter-annual variability on the fitness of migratory shorebirds. We used an individual based, biophysical migration model, driven by remotely sensed land surface data, climate data, and biological field data. Mean stop-over durations and stop-over frequency with latitude predicted from our model for nominal cases were consistent with results reported in the literature and available field data. In this study, we take advantage of new computing capabilities enabled by recent GP-GPU computing paradigms and commodity hardware (general purchase computing on graphics processing units). Several aspects of our individual based (agent modeling) approach lend themselves well to GP-GPU computing. We have been able to allocate compute-intensive tasks to the graphics processing units, and now simulate ensembles of 400,000 birds at varying spatial resolutions along the central North American flyway. We are incorporating additional, species specific, mechanistic processes to better reflect the processes underlying bird phenotypic plasticity responses to different climate change scenarios in the central U.S.

Smith, James A.↗
NASA NTRS2010

Isolation of the Paenibacillus phoenicis, a Spore-Forming Bacterium

A microorganism was isolated from the surfaces of the cleanroom facility in which the Phoenix lander was assembled. The isolated bacterial strain was subjected to a comprehensive polyphasic analysis to characterize its taxonomic position. Both phenotypic and phylogenetic analyses clearly indicate that this isolate belongs to the genus Paenibacillus and represents a novel species. Bacillus spores have been utilized to assess the degree and level of microbiological contamination on spacecraft and their associated spacecraft assembly facilities. Spores of Bacillus species are of particular concern to planetary protection due to the extreme resistance of some members of the genus to space environmental conditions such as UV and gamma radiation, vacuum, oxidation, and temperature fluctuation. These resistive spore phenotypes have enhanced potential for transfer, and subsequent proliferation, of terrestrial microbes on another solar body. Due to decreased nutrient conditions within spacecraft assembly facility clean rooms, the vegetative cells of Bacillus species and other spore-forming Paenibacillus species are induced to sporulate, thereby enhancing their survivability of bioreduction

Benardini, James N.↗
NASA NTRS2011

Effect of Microgravity on Sinorhizobium meliloti: Initial Results from the SyNRGE Experiment

SyNRGE (Symbiotic Nodulation in a Reduced Gravity Environment) was a sortie mission on STS-135 in the Biological Research in Canisters (BRIe) hardware to study the effect of microgravity on a plant-microbe symbiosis resulting in biological nitrogen fixation. Medicago truncatula, a model species of the legume family, was innoculated with its bacterial symbiont, Sinorhizobium meliloti, to observe early events associated with infection and nodulation in Petri Dish Fixation Units (PDFUs). Two sets of experiments were conducted in orbit and in 24-hour delayed ground controls. Experiment one was designed to determine if S. meliloti infect M. truncatula and initiate physiological changes associated with nodule formation. Roots of five-day-old M. truncatula cultivar Jemalong A17 (Enodll::gus) were innoculated 24 hr before launch with either S. meliloti strain 1021 or strain ABS7 and integrated into BRIC-PDFU hardware placed in a 4 C Cold Bag for launch on Atlantis. Innoculated plants and uninoculated controls were maintained in the dark at ambient temperature in the middeck of STS-135 for 11 days before fixation in RNA/ate/M by crew activation of the PDFU. Experiment two was designed to determine if microgravity altered the process of bacterial infection and host plant nodule formation. Seeds of two M. truncatula cultivar Jemalong A17 lines, the Enodll::gus used in experiment 1, and SUNN, a super-nodulating mutant of A17, were germinated on orbit for 11 days in the middeck cabin and returned to Earth alive inside of BRIC-PDFU's at 4 C S. meliloti strains 1021 and ABS7 were cultivated separately in broth culture on orbit and also returned to Earth alive. After landing, flight- and ground-grown plants and bacteria were transferred from BRIC-PDFU's into Nunc(TradeMark) 4-well plates for reciprocity crosses. Rates of plant growth and nodule development on Buffered Nodulation Medium (lacking nitrogen) were measured for 14 days. Bacteria cultivated in microgravity in the presence or absence of M. truncatula were characterized by phenotype microarray (PM) analysis of over 1,000 phenotypes including the utilization of carbon, nitrogen, phosphate, and sulfur sources; growth stimulation/inhibition by nutrients, osmolytes, and metabolic inhibitors; and antibiotic susceptibility. (Research supported by NASA ESMD/Advance Capabilities Division grant NNX10AR0

Roberts, Michael S.↗
NASA NTRS2012

Extreme Ionizing-Radiation-Resistant Bacterium

There is a growing concern that desiccation and extreme radiation-resistant, non-spore-forming microorganisms associated with spacecraft surfaces can withstand space environmental conditions and subsequent proliferation on another solar body. Such forward contamination would jeopardize future life detection or sample return technologies. The prime focus of NASA s planetary protection efforts is the development of strategies for inactivating resistance-bearing microorganisms. Eradification techniques can be designed to target resistance-conferring microbial populations by first identifying and understanding their physiologic and biochemical capabilities that confers its elevated tolerance (as is being studied in Deinococcus phoenicis, as a result of this description). Furthermore, hospitals, food, and government agencies frequently use biological indicators to ensure the efficacy of a wide range of radiation- based sterilization processes. Due to their resistance to a variety of perturbations, the non-spore forming D. phoenicis may be a more appropriate biological indicator than those currently in use. The high flux of cosmic rays during space travel and onto the unshielded surface of Mars poses a significant hazard to the survival of microbial life. Thus, radiation-resistant microorganisms are of particular concern that can survive extreme radiation, desiccation, and low temperatures experienced during space travel. Spore-forming bacteria, a common inhabitant of spacecraft assembly facilities, are known to tolerate these extreme conditions. Since the Viking era, spores have been utilized to assess the degree and level of microbiological contamination on spacecraft and their associated spacecraft assembly facilities. Members of the non-spore-forming bacterial community such as Deinococcus radiodurans can survive acute exposures to ionizing radiation (5 kGy), ultraviolet light (1 kJ/sq m), and desiccation (years). These resistive phenotypes of Deinococcus enhance the potential for transfer, and subsequent proliferation, on another solar body such as Mars and Europa. These organisms are more likely to escape planetary protection assays, which only take into account presence of spores. Hence, presences of extreme radiation-resistant Deinococcus in the cleanroom facility where spacecraft are assembled pose a serious risk for integrity of life-detection missions. The microorganism described herein was isolated from the surfaces of the cleanroom facility in which the Phoenix Lander was assembled. The isolated bacterial strain was subjected to a comprehensive polyphasic analysis to characterize its taxonomic position. This bacterium exhibits very low 16SrRNA similarity with any other environmental isolate reported to date. Both phenotypic and phylogenetic analyses clearly indicate that this isolate belongs to the genus Deinococcus and represents a novel species. The name Deinococcus phoenicis was proposed after the Phoenix spacecraft, which was undergoing assembly, testing, and launch operations in the spacecraft assembly facility at the time of isolation. D. phoenicis cells exhibited higher resistance to ionizing radiation (cobalt-60; 14 kGy) than the cells of the D. radiodurans (5 kGy). Thus, it is in the best interest of NASA to thoroughly characterize this organism, which will further assess in determining the potential for forward contamination. Upon the completion of genetic and physiological characteristics of D. phoenicis, it will be added to a planetary protection database to be able to further model and predict the probability of forward contamination.

Vaishampayan, Parag A.↗
NASA NTRS2013

Extreme Ionizing-Radiation-Resistant Bacterium

There is a growing concern that desiccation and extreme radiation-resistant, non-spore-forming microorganisms associated with spacecraft surfaces can withstand space environmental conditions and subsequent proliferation on another solar body. Such forward contamination would jeopardize future life detection or sample return technologies. The prime focus of NASA s planetary protection efforts is the development of strategies for inactivating resistance-bearing micro-organisms. Eradi cation techniques can be designed to target resistance-conferring microbial populations by first identifying and understanding their physiologic and biochemical capabilities that confers its elevated tolerance (as is being studied in Deinococcus phoenicis, as a result of this description). Furthermore, hospitals, food, and government agencies frequently use biological indicators to ensure the efficacy of a wide range of radiation-based sterilization processes. Due to their resistance to a variety of perturbations, the nonspore forming D. phoenicis may be a more appropriate biological indicator than those currently in use. The high flux of cosmic rays during space travel and onto the unshielded surface of Mars poses a significant hazard to the survival of microbial life. Thus, radiation-resistant microorganisms are of particular concern that can survive extreme radiation, desiccation, and low temperatures experienced during space travel. Spore-forming bacteria, a common inhabitant of spacecraft assembly facilities, are known to tolerate these extreme conditions. Since the Viking era, spores have been utilized to assess the degree and level of microbiological contamination on spacecraft and their associated spacecraft assembly facilities. Members of the non-sporeforming bacterial community such as Deinococcus radiodurans can survive acute exposures to ionizing radiation (5 kGy), ultraviolet light (1 kJ/m2), and desiccation (years). These resistive phenotypes of Deinococcus enhance the potential for transfer, and subsequent proliferation, on another solar body such as Mars and Europa. These organisms are more likely to escape planetary protection assays, which only take into account presence of spores. Hence, presences of extreme radiation-resistant Deinococcus in the cleanroom facility where spacecraft are assembled pose a serious risk for integrity of life-detection missions. The microorganism described herein was isolated from the surfaces of the cleanroom facility in which the Phoenix Lander was assembled. The isolated bacterial strain was subjected to a comprehensive polyphasic analysis to characterize its taxonomic position. This bacterium exhibits very low 16SrRNA similarity with any other environmental isolate reported to date. Both phenotypic and phylogenetic analyses clearly indicate that this isolate belongs to the genus Deinococcus and represents a novel species. The name Deinococcus phoenicis was proposed after the Phoenix spacecraft, which was undergoing assembly, testing, and launch operations in the spacecraft assembly facility at the time of isolation. D. phoenicis cells exhibited higher resistance to ionizing radiation (cobalt-60; 14 kGy) than the cells of the D. radiodurans (5 kGy). Thus, it is in the best interest of NASA to thoroughly characterize this organism, which will further assess in determining the potential for forward contamination. Upon the completion of genetic and physiological characteristics of D. phoenicis, it will be added to a planetary protection database to be able to further model and predict the probability of forward contamination.

Vaishampayan, Parag A.↗
NASA NTRS2014

Salt Tolerance and Polyphyly in the Cyanobacterium Chroococcidiopsis (Pleurocapsales)1

Chroococcidiopsis Geitler (Geitler 1933) is a genus of cyanobacteria containing desiccation and radiation resistant species. Members of the genus live in habitats ranging from hot and cold deserts to fresh and saltwater environments. Morphology and cell division pattern have historically been used to define the genus. To better understand the genetic and phenotypic diversity of the genus, 15 species were selected that had been previously isolated from different locations, including salt and freshwater environments. Four markers were sequenced from these 15 species, the 16S rRNA, rbcL, desC1 and gltX genes. Phylogenetic trees were generated which identified two distinct clades, a salt-tolerant clade and a freshwater clade. This study demonstrates that the genus is polyphyletic based on saltwater and freshwater phenotypes. To understand the resistance to salt in more details, species were grown on a range of sea salt concentrations which demonstrated that the freshwater species were salt-intolerant whilst the saltwater species required salt for growth. This study shows an increased resolution of the phylogeny of Chroococcidiopsis and provides further evidence that the genus is polyphyletic and should be reclassified to improve clarity in the literature.

Genus↗
NASA NTRS2015

Expression of Genes Involved in Drosophila Wing Morphogenesis and Vein Patterning Are Altered by Spaceflight

Imaginal wing discs of Drosophila melanogaster (fruit fly) defined during embryogenesis ultimately result in mature wings of stereotyped (specific) venation patterning. Major regulators of wing disc development are the epidermal growth factor receptor (EGF), Notch, Hedgehog (Hh), Wingless (Wg), and Dpp signaling pathways. Highly stereotyped vascular patterning is also characteristic of tissues in other organisms flown in space such as the mouse retina and leaves of Arabidopsis thaliana. Genetic and other adaptations of vascular patterning to space environmental factors have not yet been systematically quantified, despite widespread recognition of their critical importance for terrestrial and microgravity applications. Here we report changes in gene expression with space flight related to Drosophila wing morphogenesis and vein patterning. In addition, genetically modified phenotypes of increasingly abnormal ectopic wing venation in the Drosophila wing1 were analyzed by NASA's VESsel GENeration Analysis (VESGEN) software2. Our goal is to further develop insightful vascular mappings associated with bioinformatic dimensions of genetic or other molecular phenotypes for correlation with genetic and other molecular profiling relevant to NASA's GeneLab and other Space Biology exploration initiatives.

venation↗
NASA NTRS2016

Analysis of Adult Female Mouse (Mus musculus) Group Behavior on the International Space Station (ISS)

As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. A handful of papers have previously reported behavior of mice and rats in the weightless environment of space. The Rodent Research Hardware and Operations Validation (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS (International Space Station). Ten adult (16-week-old) female C57BL/6 mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in microgravity. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the Rodent Habitat (RH) during this long-duration flight. Video was recorded for 33 days on the ISS, permitting daily assessments of overall health and well-being of the mice, and providing a valuable repository for detailed behavioral analysis. We previously reported that, as compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allo-grooming, and social interactions at similar or greater levels of occurrence. Overall activity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized 'circling' or 'race-tracking' behavior that emerged within the first few days of flight following a common developmental sequence, and comprised the primary dark cycle activity persisting throughout the remainder of the experiment. Participation by individual mice increased dramatically over the course of the flight. Here we present a detailed analysis of 'race-tracking' behavior in which we quantified: (1) Complete lap rotations by individual mice; (2) Numbers of collisions between circling mice; (3) Lap directionality; and (4) Recruitment of mice into a group phenotype. This analysis contributes to the first NASA long-duration study of rodent behavior, providing evidence for the emergence of a distinctive, organized group behavior unique to the weightless space environment.

Behavior in Space↗
NASA NTRS2017

Integrated Model of the Eye/Optic Nerve Head Biomechanical Environment

Visual Impairment and Intracranial Pressure (VIIP) syndrome is a concern for long-duration space flight. Previously, it has been suggested that ocular changes observed in VIIP syndrome are related to the cephalad fluid shift that results in altered fluid pressures [1]. We are investigating the impact of changes in intracranial pressure (ICP) using a combination of numerical models, which simulate the effects of various environment conditions, including finite element (FE) models of the posterior eye. The specific interest is to understand how altered pressures due to gravitational changes affect the biomechanical environment of tissues of the posterior eye and optic nerve sheath. METHODS: Additional description of the numerical modeling is provided in the IWS abstract by Nelson et al. In brief, to simulate the effects of a cephalad fluid shift on the cardiovascular and ocular systems, we utilized a lumped-parameter compartment model of these systems. The outputs of this lumped-parameter model then inform boundary conditions (pressures) for a finite element model of the optic nerve head (Figure 1). As an example, we show here a simulation of postural change from supine to 15 degree head-down tilt (HDT), with primary outcomes being the predicted change in strains at the optic nerve head (ONH) region, specifically in the lamina cribrosa (LC), retrolaminar optic nerve, and prelaminar neural tissue (PLNT). The strain field can be decomposed into three orthogonal components, denoted as the first, second and third principal strains. We compare the peak tensile (first principal) and compressive (third principal) strains, since elevated strain alters cell phenotype and induces tissue remodeling. RESULTS AND CONCLUSIONS: Our lumped-parameter model predicted an IOP increase of c. 7 mmHg after 21 minutes of 15 degree HDT, which agreed with previous reports of IOP in HDT [1]. The corresponding FEM simulations predicted a relative increase in the magnitudes of the peak tensile and compressive strains in the lamina cribrosa of 42 and 43, respectively (Fig. 2). The corresponding changes in the optic nerve strains were 17 and 39, while in the PLNT they were 47 and 43. These magnitudes of relative elevations in peak strains may induce a phenotypic response in resident mechano-responsive resident cells [2]. This approach may be expanded to investigate other environmental changes (e.g. parabolic flight). Through our VIIP SCHOLAR project, we will validate and improve these integrated models by measuring patient-specific changes in optic nerve sheath geometry in patients with idiopathic intracranial hypertension before and after lumbar puncture and CSF removal.

biomechanics↗
NASA NTRS2017

Mouse Behavior on ISS: The Emergence of a Distinctive, Organized Group Circling Behavior Unique to Spaceflight

As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. Only a handful of papers have previously reported behavior of mice and rats in the weightless environment of space (Andreev-Andrievskiy, et al., 2013; Cancedda et al., 2012; Ronca et al., 2008). The Rodent Research Hardware and Operations Validation Mission (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS. Ten adult (16-week-old) female C57BL6J mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in flight. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the RH during this long duration flight. Video was recorded for 34 days on the ISS, permitting daily assessments of overall health and well being of the mice, and providing a valuable repository for detailed behavioral analysis. As compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allogrooming, and social interactions at similar or greater levels of occurrence. Overall activity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized circling or race-tracking behavior that emerged within the first few days of flight following a common developmental sequence, comprising the primary dark cycle activity of FLT mice. Circling participation by individual mice persisted throughout the mission. Analysis of group behavior over mission days revealed recruitment of mice into the group phenotype, coupled with decreasing numbers of collisions between circling mice. This analysis provides insights into the behavior of mice in microgravity, and clear evidence for the emergence of a distinctive, organized group behavior unique to the weightless space environment. Supported by the NASA Rodent Research Project, Space Biology Program, and Space Life Sciences Training Program.

spaceflight↗
NASA NTRS2017

Mouse Behavior on ISS: The Emergence of Distinctive, Organized Group Circling Behavior Unique to Spaceflight

As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. Only a handful of papers have previously reported behavior of mice and rats in the weightless environment of space (Andreev-Andrievskiy, et al., 2013; Cancedda et al., 2012; Ronca et al., 2008). The Rodent Research Hardware and Operations Validation Mission (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS. Ten adult (16-week-old) female C57BL6J mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in flight. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the RH during this long duration flight. Video was recorded for 34 days on the ISS, permitting daily assessments of overall health and well being of the mice, and providing a valuable repository for detailed behavioral analysis. As compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allogrooming,and social interactions at similar or greater levels of occurrence. Overallactivity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized circling or race-tracking behavior that emerged within thefirst few days of flight following a common developmental sequence, comprising theprimary dark cycle activity of FLT mice. Circling participation by individual micepersisted throughout the mission. Analysis of group behavior over mission days revealed recruitment of mice into the group phenotype, coupled with decreasing numbers of collisions between circling mice. This analysis provides insights into the behavior of mice in microgravity, and clear evidence for the emergence of a distinctive,organized group behavior unique to the weightless space environment.

mice↗
NASA NTRS2018

Persistence of Gamma-H2AX Foci in Irradiated Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice

The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in their ability to efficiently repair DNA double strand breaks resulting from radiation exposure. We phenotyped mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA double strand breaks during protracted radiation exposures. We monitored persistent gamma-H2AX radiation induced foci (RIF) 24 hours after exposure to chronic gamma-rays as a surrogate marker for repair deficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/cHeN founder strain. We observed a very strong correlation R2 = 79.18%, P < 0.001) between the level of persistent RIF and radiogenic lung cancer percent incidence measured in the same strains. Interestingly, spontaneous levels of foci in non-irradiated strains also showed good correlation with lung cancer incidence (R2=32.74%, P =0.013). These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains and that high levels of spontaneous DNA damage is also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that such phenotyping assay could be used to detect radiogenic lung cancer susceptibility in humans.

Ochola, Donasian O.↗
NASA NTRS2017

Bone and Cartilage Degeneration in Mice Following Long-Duration Spaceflight: The Role of Bone Marrow Stem Cells

The detrimental effects of mechanical unloading in microgravity, including the musculo-skeletal system, are well documented. However, the effects of mechanical unloading on joint health and the interaction between bone and cartilage specifically, are less well known. Our ongoing studies with the mouse bone model have identified the failure of normal stem cell-based tissue regeneration, in addition to tissue degeneration, as a significant concern for long-duration spaceflight, especially in the mesenchymal and hematopoietic tissue lineages. Furthermore, we have identified the cell cycle arrest molecule, CDKN1ap21, as specifically up-regulated during spaceflight exposure and localized to osteoprecursors on the bone surface and chondroprogenitors in articular cartilage that are both required for normal tissue regeneration. The 30-day BionM1 and 37-day Rodent Research 1 (RR1) missions enabled the possibility of studying these effects in long-duration microgravity experiments. We hypothesized that the inhibition of stem cell-based tissue regeneration in short-duration spaceflight would continue during long-duration spaceflight resulting in significant tissue alterations and we specifically studied the hip joint (pelvis and proximal femur) to elucidate these effects. To test this hypothesis we analyzed bone and bone marrow stem cells using techniques including high-resolution Microcomputed Tomography (MicroCT), in-vivo differentiation and migration assays, and whole transcriptome expression profiling. We found that exposure to spaceflight for 30 days results in a significant decrease in bone volume fraction (-31), trabecular thickness (-14) and trabecular number (-20). Similar decrements in bone volume fraction (-27), trabecular number (-13) and trabecular thickness (-17) were found in female mice exposed to 37 days spaceflight. Furthermore, high-resolution MicroCT and immunohistochemical analysis of spaceflight tissues revealed a severe disruption of the epiphyseal boundary, resulting in endochondral ossification of the femoral head and perforation of articular cartilage by bone. This suggests that spaceflight in microgravity may cause rapid induction of an aging-like phenotype with signs of osteoarthritic disease in the hip joint. Microarray analysis also revealed that the top pathways altered during spaceflight include activation of matrix metalloproteinases, oxidative stress signaling and inflammation in both whole bone tissue and isolated bone marrow stem cells. In conclusion, the observed inhibition of stem cell-based tissue regeneration persists during long-duration spaceflight. Furthermore, spaceflight mice exhibit disruption of the epiphyseal boundary and endochondral ossification of the femoral head, and an inhibition of stem cell based tissue regeneration, which, taken together, may indicate onset of an accelerated aging phenotype with signs of osteoarthritic disease.

Cartilage↗
NASA NTRS2019

Prenatal 2g Exposure Alters Placental Expression of Stress-Related Genes

Extra-terrestrial colonization is of growing interest to space agencies and private entities, emphasizing the importance of research on reproduction and development in the absence of Earth's 1G. Maternal stressors can modify offspring development, exerting significant lifespan and crossgenerational changes through prenatal programming. The space environment is stressful, therefore exposure to altered gravity during pregnancy may impact later life outcomes in offspring. In ground-based studies, we exposed pregnant rats to continuous +G (above Earth gravity), and observed overweight and elevated anxiety in adult male (but not female) offspring, common phenotypes associated with prenatal maternal stress. Here we hypothesize that exposure to increased gravity during pregnancy elicits changes in the expression of stress-related genes in placenta that may mediate emergence of later life outcomes. While the placenta transports maternal factors to the fetus and produces endogenous fetal hormones, stress-induced changes at the placental-uterine interface may also alter communication between mother and fetus, facilitating prenatal transmission of unfavorable later life outcomes and cross-generational epigenetic alterations. Maternal stress elevates maternal glucocorticoids however placental 11b-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers fetal exposure by converting cortisol/corticosterone into inactive metabolites. Maternal stress during pregnancy down-regulates this enzyme and can induce epigenetic changes in placental and fetal tissues accounting for heightened adult HPA reactivity. Past studies have shown a placenta-specific increase in DNA methyltransferase (DNMT3a) mRNA in stressed mothers, an effect with implications for genome-wide epigenetic changes that may account for diverse phenotypic outcomes following maternal stress. Here we exposed groups of pregnant rats to one of five gravity loads (1, 1.5, 1.75 and 2G) and analyzed placental samples during late gestation. We predicted a systematic dose-response relationship between gravity load and the expression of the HSD11B2 and DNMT3 genes, thereby linking maternal exposure to altered gravity during pregancy with maternal stress.

Kalotia, Simranjit K.↗