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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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NASA NTRS1996

Modulation by cyclic GMP of the odour sensitivity of vertebrate olfactory receptor cells

Recent evidence has indicated a significant role for the cGMP second messenger system in vertebrate olfactory transduction but no clear functions have been identified for cGMP so far. Here, we have examined the effects of 8-Br-cGMP and carbon monoxide (CO) on odour responses of salamander olfactory receptor neurons using perforated patch recordings. We report that 8-Br-cGMP strongly down-regulates the odour sensitivity of the cells, with a K1/2 of 460 nM. This adaptation-like effect can be mimicked by CO, an activator of soluble guanylyl cyclase, with a K1/2 of 1 microM. Sensitivity modulation is achieved through a regulatory chain of events in which cGMP stimulates a persistent background current due to the activation of cyclic nucleotide-gated channels. This in turn leads to sustained Ca2+ entry providing a negative feedback signal. One consequence of the Ca2+ entry is a shift to the right of the stimulus-response curve and a reduction in saturating odour currents. Together, these two effects can reduce the sensory generator current by up to twenty-fold. Thus, cGMP functions to control the gain of the G-protein coupled cAMP pathway. Another consequence of the action of cGMP is a marked prolongation of the odour response kinetics. The effects of CO/cGMP are long-lasting and can continue for minutes. Hence, we propose that cGMP helps to prevent saturation of the cell's response by adjusting the operational range of the cAMP cascade and contributes to olfactory adaptation by decreasing the sensitivity of olfactory receptor cells to repeated odour stimuli.

NASA Discipline Neuroscience↗
NASA NTRS2007

Radiative and Physiological Effects of Increased CO2. How does this interaction affect Climate in the Mediterranean Region?

the radiative and physiological effects of doubled atmospheric carbon dioxide concentration (CO2) on climate are described using climate simulations. When CO2 was increased for vegetation only assuming no radiative effect, the response was a decrease in stomatal conductance followed by a temperature increase. This temperature increase was stronger when the vegetation physiological down-regulation was allowed in the model. The radiative forcing alone did not affect the global mean photosynthesis, however, some stimulation was observed in cold places. The interactions between the physiological and the radiative effects of doubled CO2 are not linearly additive and when acting together they tend to reduce the warming in the Mediterranean region.

Bounoua, Lahouari↗
NASA NTRS2008

Adaptation of the Skeletal System during Long-duration Spaceflight

This review will highlight evidence from crew members flown on space missions greater than 90 days to suggest that the adaptations of the skeletal system to mechanical unloading may predispose crew members to an accelerated onset of osteoporosis after return to Earth. By definition, osteoporosis is a skeletal disorder - characterized by low bone mineral density and structural deterioration - that reduces the ability of bones to resist fracture under the loading of normal daily activities. Involutional or agerelated osteoporosis is readily recognized as a syndrome afflicting the elderly population because of the insipid and asymptomatic nature of bone loss that does not typically manifest as fractures until after age approximately 60. It is not the thesis of this review to suggest that spaceflight-induced bone loss is similar to bone loss induced by metabolic bone disease; rather this review draws parallels between the rapid and earlier loss in females that occurs with menopause and the rapid bone loss in middle-aged crew members that occurs with spaceflight unloading and how the cumulative effects of spaceflight and ageing could be detrimental, particularly if skeletal effects are totally or partially irreversible. In brief, this report will provide detailed evidence that long-duration crew members, exposed to the weightlessness of space for the typical long-duration (4-6 months) mission on Mir or the International Space Station -- 1. Display bone resorption that is aggressive, that targets normally weight-bearing skeletal sites, that is uncoupled to bone formation and that results in areal BMD deficits that can range between 6-20% of preflight BMD; 2. Display compartment-specific declines in volumetric BMD in the proximal femur (a skeletal site of clinical interest) that significantly reduces its compressive and bending strength and which may account for the loss in hip bone strength (i.e., force to failure); 3. Recover BMD over a post-flight time period that exceeds spaceflight exposure but for which the restoration of whole bone strength remains an open issue and may involve structural alteration; and 4. Display risk factors for bone loss -- such as the negative calcium balance and down-regulated calcium-regulating hormones in response to bone atrophy -- that can be compounded by the constraints of conducting mission operations (inability to provide essential nutrients and vitamins). The full characterization of the skeletal response to mechanical unloading in space is not complete. In particular, countermeasures used to date have been inadequate and it is not yet known whether more appropriate countermeasures can prevent the changes in bone that have been found in previous flights, knowledge gaps related to the effects of prolonged (greater than or equal to 6 months) space exposure and to partial gravity environments are substantial, and longitudinal measurements on crew members after spaceflight are required to assess the full impact on skeletal recovery.

Sibonga, Jean D.↗
NASA NTRS2006

Immune Response in Microgravity: Genetic Basis and Countermeasure Development Implications

Impairment of the immunity in astronauts and cosmonauts even in shortterm flights is a recognized risk. Longterm orbital space missions and anticipated interplanetary flights increase the concern for more pronounced effects on the immune system with potential clinical consequences. Studies in true and modeled microgravity (MG) have demonstrated that MG directly affects numerous lymphocyte functions. The purpose of this study was to screen for genes involved in lymphocytes response to modeled microgravity (MMG) that could explain the functional and structural changes observed earlier. The microgravity-induced changes in gene expression were analyzed by microarray DNA chip technology. CD3and IL2activated Tcells were cultured in 1g (static) and modeled microgravity (NASA Rotating Wall Vessel bioreactor) conditions for 24 hours. Total RNA was extracted using the RNeasy isolation kit (Qiagen, Valencia, CA). Microarray experiments were performed utilizing Affymetrix Gene Chips (U133A), allowing testing for 18,400 human genes. To decrease the biological variation and aid in detecting microgravity-associated changes, experiments were performed in triplicate using cells obtained from three different donors. Exposure to modeled microgravity resulted in alteration of 89 genes, 10 of which were upregulated and 79 down-regulated. Altered genes were categorized by their function, structural role and by association with metabolic and regulatory pathways. A large proportion was found to be involved in fundamental cellular processes: signal transduction, DNA repair, apoptosis, and multiple metabolic pathways. There was a group of genes directly related to immune and inflammatory responses (IL7R, granulysin, proteasome activator subunit 2, peroxiredoxin 4, HLADRA, lymphocyte antigen 75, IL18R and DOCK2 genes). Among these genes only one (IL7R) was upregulated, the rest were downregulated. The upregulation of the IL7 receptor gene was confirmed by RT PCR. Three genes with altered expression were identified in the apoptosis related group (Granzyme B, APO2 ligand and Beta3endonexin). All of them were downregulated. Gene expression changes in MG might appear pivotal in identifying potential molecular targets for countermeasure development. (Supported by NRA OLMSA02 and NSCORT NAG54072 grants).

Risin, Diana↗
NASA NTRS2010

Molecular and Histopathological Changes in Mouse Intestinal Tissue After Proton Exposure

Whole body exposure to protons in mice causes significant apoptosis in the crypts of the small intestine. Increasing numbers of crypts contained more apoptotic lesions as the dose of exposure increased. 16 genes associated with apoptotic pathways were shown to have significantly altered expression as compared to control samples for at least one of the doses of proton exposure 1 gene, Trp53inp1, was significantly up-regulated across all three doses. Those animals exposed to 0.1 Gy of proton irradiation showed greater amounts of significant alterations in gene expression as compared to 1 Gy and 2 Gy exposures. The differences in gene expression changes of low and high dose proton irradiated mice may offer insight into the molecular mechanisms of the possible high sensitivity at low proton doses. RAIDD (CRADD) may be responsible for the hypersensitivity observed in the duodenum of mice exposed to low doses of protons. Caspase-1 may also play a role in the hypersensitivity seen following proton irradiation at a dose of 0.1 Gy. FOXO3A may be involved in the down-regulation of GILZ observed at high doses of proton exposure.

Purgason, Ashley↗
NASA NTRS2000

Nutritional Biochemistry of Space Flight

Adequate nutrition is critical for maintenance of crew health during and after extended-duration space flight. The impact of weightlessness on human physiology is profound, with effects on many systems related to nutrition, including bone, muscle, hematology, fluid and electrolyte regulation. Additionally, we have much to learn regarding the impact of weightlessness on absorption, m~tabolism , and excretion of nutrients, and this will ultimately determine the nutrient requirements for extended-duration space flight. Existing nutritional requirements for extended-duration space flight have been formulated based on limited flight research, and extrapolation from ground-based research. NASA's Nutritional Biochemistry Laboratory is charged with defining the nutritional requirements for space flight. This is accomplished through both operational and research projects. A nutritional status assessment program is included operationally for all International Space Station astronauts. This medical requirement includes biochemical and dietary assessments, and is completed before, during, and after the missions. This program will provide information about crew health and nutritional status, and will also provide assessments of countermeasure efficacy. Ongoing research projects include studies of calcium and bone metabolism, and iron absorption and metabolism. The calcium studies include measurements of endocrine regulation of calcium homeostasis, biochemical marker~ of bone metabolism, and tracer kinetic studies of calcium movement in the body. These calcium kinetic studies allow for estimation of intestinal absorption, urinary excretion, and perhaps most importantly - deposition and resorption of calcium from bone. The Calcium Kinetics experiment is currently being prepared for flight on the Space Shuttle in 2001, and potentially for subsequent Shuttle and International Space Station missions. The iron study is intended to assess whether iron absorption is down-regulated dUl1ng space flight. This is critical due to the red blood cell changes which occur, and the increase in iron storage that has been observed after space flight. The Iron Absorption and Metabolism experiment is currently planned for long-term flights on the International Space Station.

Smith, Scott M.↗
NASA NTRS2001

Spaceflight Did Not Impair Cardiovascular Responses to Upright Posture in an Elderly Astronaut

Some of the cardiovascular changes associated with spaceflight have similarities to those associated with aging. We studied the neuroendocrine and hemodynamic responses to upright posture in a 77 year old astronaut before and after spaceflight and compared them to those of a group of 20 younger (41 plus or minus 1 years) astronauts. While arterial pressure responses to standing were similar between the young and old astronauts, hemodynamic profiles were quite different. The elderly astronaut achieved adequate standing arterial pressure primarily by maintaining stroke volume and thus cardiac output. In spite of very high norepinephrine release, he had very little increase in heart rate or total peripheral resistance. This pattern persisted on all test occasions. These responses suggest high sympathetic responses, down-regulated adrenergic receptors and decreased venous compliance typical of aging. In contrast, younger astronauts did not maintain stroke volume or cardiac output with standing, but had significant increases in heart rate and resistance. These results suggest that this elderly subject had cardiovascular responses to standing that are expected in an aged person. These responses were not deleteriously affected by spaceflight. We suggest that healthy, fit elderly individuals are able to withstand the stresses of extreme environments and are not necessarily limited in their activities simply due to their chronological age.

Rossum, Alfred C.↗
NASA NTRS2003

Modeled Microgravity-Induced Protein Kinase C Isoform Expression in Human Lymphocytes

In long-term space travel, the crew is exposed to microgravity and radiation that invoke potential hazards to the immune system. T cell activation is a critical step in the immune response. Receptor-mediated signaling is inhibited both in microgravity and modeled microgravity (MMG) as reflected in diminished DNA synthess in peripheral blood lymphocytes and their locomotion through gelled type 1 collagen. Direct activation of Protein Kinase C (PKC) bypassing cell surface events using the phorbol ester PMA rescues MMG-inhibited lymphocyte activation and locomotion, whereas calcium ionophore ionomycin had no rescue effect. Thus calcium-independent PKC isoforms may be affected in MMG-induced locomotion inhibition and rescue. Both calcium-dependent isoforms and calcium-independent PKC isoforms were investigated to assess their expression in lymphocytes in 19 and MMG-culture. Human lymphocytes were cultured and harvested at 24, 48, 72 and 96 hours and serial samples assessed for locomotion using type I collagen and expression of PKC isoforms. Expression of PKC-alpha, -delta and -epsilon was assessed by RT-PCR, flow cytometry and immunoblotting. Results indicated that PKC isoforms delta and epsilon were down-regulated by more than 50% at the transcriptional and translational levels in MMG-cultured lymphocytes compared with 19 controls. Events upstream of PKC such as phosphorylation of Phospholipase C(gamma) (PLC-gamma) in MMG, revealed accumulation of inactive enzyme. Depressed Ca++ -independent PKC isoforms may be a consequence of an upstream lesion in the signal transduction pathway. The differential response among calcium-dependent and calcium-independent isoforms may actually result from MMG intrusion events earlier than, but after ligand-receptor interaction. Keywords: Signal transduction, locomotion, immunity

Sundaresan, A.↗
NASA NTRS2010

A Comparison of Molecular and Histopathological Changes in Mouse Intestinal Tissue Following Whole-Body Proton- or Gamma-Irradiation

There are many consequences following exposure to the space radiation environment which can adversely affect the health of a crew member. Acute radiation syndrome (ARS) involving nausea and vomiting, damage to radio-sensitive tissue such as the blood forming organs and gastrointestinal tract, and cancer are some of these negative effects. The space radiation environment is ample with protons and contains gamma rays as well. Little knowledge exists to this point, however, regarding the effects of protons on mammalian systems; conversely several studies have been performed observing the effects of gamma rays on different animal models. For the research presented here, we wish to compare our previous work looking at whole-body exposure to protons using a mouse model to our studies of mice experiencing whole-body exposure to gamma rays as part of the radio-adaptive response. Radio-adaptation is a well-documented phenomenon in which cells exposed to a priming low dose of radiation prior to a higher dose display a reduction in endpoints like chromosomal aberrations, cell death, micronucleus formation, and more when compared to their counterparts receiving high dose-irradiation only. Our group has recently completed a radio-adaptive experiment with C57BL/6 mice. For both this study and the preceding proton research, the gastrointestinal tract of each animal was dissected four hours post-irradiation and the isolated small intestinal tissue was fixed in formalin for histopathological examination or snap-frozen in liquid nitrogen for RNA isolation. Histopathologic observation of the tissue using standard H&E staining methods to screen for morphologic changes showed an increase in apoptotic lesions for even the lowest doses of 0.1 Gy of protons and 0.05 Gy of gamma rays, and the percentage of apoptotic cells increased with increasing dose. A smaller percentage of crypts showed 3 or more apoptotic lesions in animals that received 6 Gy of gamma-irradiation compared to mice receiving only 2 Gy of protons. Tissue of the gastrointestinal tract was also homogenized and RNA was isolated for cDNA synthesis and real-time PCR analysis. Inspecting apoptotic lesions of the duodenum of the small intestine as an endpoint of damage did not reveal a radio-adaptive response in C57BL/6 mice at the four hour time point. Results of gene expression changes showed consistent up or down regulation of a number of genes for all of the exposure doses that may play a role in proton-induced apoptosis. Preliminary results of gene expression alterations as a result of gamma-irradiation revealed a wealth of genes involved in oxidative stress and antioxidant defense processes being up- or down-regulated only at the highest exposure dose of 6 Gy and the combined dose of 5 cGy with 6 Gy. Those animals undergoing only 5 cGy of gamma-irradiation showed very little modification of gene expression. Taken together these results lead us to conclude that protons cause more severe morphologic damage to the duodenum of the small intestine at a dose of 2 Gy than a higher dose of 6 Gy of gamma rays to the same organ. Both protons and gamma rays lead to significant variation in gene expression at high doses in the small intestine and these changes may provide insight into the mechanism of injury seen in the gastrointestinal tract following radiation exposure. Astronauts experiencing prolonged exposure to protons in the low Earth orbit and in deep space, and experiencing acute exposure to protons from solar particle events, may face biological consequences that will impact a mission s success. We will continue this work by studying, quantifying, and comparing damage due to protons and gamma rays in the small intestine as well as other organs in a time-dependent manner.

Purgason, Ashley↗
NASA NTRS2011

Low Fluid Shear Culture of Staphylococcus Aureus Represses hfq Expression and Induces an Attachment-Independent Biofilm Phenotype

Background: The opportunistic pathogen, Staphylococcus aureus, experiences fluctuations in fluid shear during infection and colonization of a human host. Colonization frequently occurs at mucus membrane sites such as in the gastrointestinal tract where the bacterium may experience low levels of fluid shear. The response of S. aureus to low fluid shear remains unclear. Methods: S. aureus was cultured to stationary phase using Rotating-Wall Vessel (RWV) bioreactors which produce a physiologically relevant low fluid shear environment. The bacterial aggregates that developed in the RWV were evaluated by electron microscopy as well as for antibiotic resistance and other virulence-associated stressors. Genetic expression profiles for the low-shear cultured S. aureus were determined by microarray analysis and quantitative real-time PCR. Results: Planktonic S. aureus cultures in the low-shear environment formed aggregates completely encased in high amounts of extracellular polymeric substances. In addition, these aggregates demonstrated increased antibiotic resistance indicating attachment-independent biofilm formation. Carotenoid production in the low-shear cultured S. aureus was significantly decreased, and these cultures displayed an increased susceptibility to oxidative stress and killing by whole blood. The hfq gene, associated with low-shear growth in Gram negative organisms, was also found to be down-regulated in S. aureus. Conclusions: Collectively, this data suggests that S. aureus decreases virulence characteristics in favor of a biofilm-dwelling colonization phenotype in response to a low fluid shear environment. Furthermore, the identification of an Hfq response to low-shear culture in S. aureus, in addition to the previously reported responses in Gram negative organisms, strongly suggests an evolutionarily conserved response to mechanical stimuli among structurally diverse prokaryotes.

Ott, C. Mark↗
NASA NTRS2010

Quantifying the Negative Feedback of Vegetation to Greenhouse Warming: A Modeling Approach

Several climate models indicate that in a 2 x CO2 environment, temperature and precipitation would increase and runoff would increase faster than precipitation. These models, however, did not allow the vegetation to increase its leaf density as a response to the physiological effects of increased CO2 and consequent changes in climate. Other assessments included these interactions but did not account for the vegetation down-regulation to reduce plant's photosynthetic activity and as such resulted in a weak vegetation negative response. When we combine these interactions in climate simulations with 2 x CO2, the associated increase in precipitation contributes primarily to increase evapotranspiration rather than surface runoff, consistent with observations, and results in an additional cooling effect not fully accounted for in previous simulations with elevated CO2. By accelerating the water cycle, this feedback slows but does not alleviate the projected warming, reducing the land surface warming by 0.6 C. Compared to previous studies, these results imply that long term negative feedback from CO2-induced increases in vegetation density could reduce temperature following a stabilization of CO2 concentration.

Bounous, L.↗
NASA NTRS2014

Gene Expression Changes in Mouse Intestinal Tissue Following Whole-Body Proton or Gamma-Irradiation

Crew members face potential consequences following exposure to the space radiation environment including acute radiation syndrome and cancer. The space radiation environment is ample with protons, and numerous studies have been devoted to the understanding of the health consequences of proton exposures. In this project, C57BL/6 mice underwent whole-body exposure to 250 MeV of protons at doses of 0, 0.1, 0.5, 2 and 6 Gy and the gastrointestinal (GI) tract of each animal was dissected four hours post-irradiation. Standard H&E staining methods to screen for morphologic changes in the tissue showed an increase in apoptotic lesions for even the lowest dose of 0.1 Gy, and the percentage of apoptotic cells increased with increasing dose. Results of gene expression changes showed consistent up- or down- regulation, up to 10 fold, of a number of genes across exposure doses that may play a role in proton-induced oxidative stress including Gpx2. A separate study in C57BL/6 mice using the same four hour time point but whole-body gamma-irradiation showed damage to the small intestine with lesions appearing at the smallest dose of 0.05 Gy and increasing with increasing absorbed dose. Expressions of genes associated with oxidative stress processes were analyzed at four hours and twenty-four hours after exposure to gamma rays. We saw a much greater number of genes with significant up- or down-regulation twenty-four hours post-exposure as compared to the four hour time point. At both four hours and twenty-four hours post-exposure, Duox1 and Mpo underwent up-regulation for the highest dose of 6 Gy. Both protons and gamma rays lead to significant variation in gene expressions and these changes may provide insight into the mechanism of injury seen in the GI tract following radiation exposure. We have also completed experiments using a BALB/c mouse model undergoing whole-body exposure to protons. Doses of 0, 0.1, 1 and 2 Gy were used and results will be compared to the work mentioned above. The most striking result preliminarily is that both strains of mice show a greater number of genes changing at the lowest dose of exposure for their respective pathways.

Purgason, Ashley↗
NASA NTRS2015

Genetically Engineered Cyanobacteria

The disclosed embodiments provide cyanobacteria spp. that have been genetically engineered to have increased production of carbon-based products of interest. These genetically engineered hosts efficiently convert carbon dioxide and light into carbon-based products of interest such as long chained hydrocarbons. Several constructs containing polynucleotides encoding enzymes active in the metabolic pathways of cyanobacteria are disclosed. In many instances, the cyanobacteria strains have been further genetically modified to optimize production of the carbon-based products of interest. The optimization includes both up-regulation and down-regulation of particular genes.

Zhou, Ruanbao↗
NASA NTRS2017

Systemic Response to Microgravity: Utilizing GeneLab Datasets to Identify Molecular Targets for Future Hypotheses-Driven Spaceflight Studies

Biological risks associated with microgravity are a major concern for long-term space travel. Although determination of risk has been a focus for NASA research, data examining systemic (i.e., multi- or pan-tissue) responses to space flight are sparse. To perform our analysis, we utilized the NASA GeneLab database which is a publicly available repository containing a wide array of omics results from experiments conducted with: i) with different flight conditions (space shuttle (STS) missions vs. International Space Station (ISS); ii) a variety of tissues; and 3) assays that measure epigenetic, transcriptional, and protein expression changes. Meta-analysis of the transcriptomic data from 7 different murine and rat data sets, examining tissues such as liver, kidney, adrenal gland, thymus, mammary gland, skin, and skeletal muscle (soleus, extensor digitorum longus, tibialis anterior, quadriceps, and gastrocnemius) revealed for the first time, the existence of potential master regulators coordinating systemic responses to microgravity in rodents. We identified p53, TGF(beta)1 and immune related pathways as the highly prevalent pan-tissue signaling pathways that are affected by microgravity. Some variability in the degree of change in their expression across species, strain and time of flight was also observed. Interestingly, while certain skeletal muscle (gastrocnemius and soleus) exhibited an overall down-regulation of these genes, some other muscle types such as the extensor digitorum longus, tibialis anterior and quadriceps, showed an up-regulated expression, indicative of potential compensatory mechanisms to prevent microgravity-induced atrophy. Key genes isolated by unbiased systems analyses displayed a major overlap between tissue types and flight conditions and established TGF(beta)1 to be the most connected gene across all data sets. Finally, a set of microgravity responsive miRNA signature was identified and based on their predicted functional state and subsequent impact on health, a theoretical health risk score was calculated. The genes and miRNAs identified from our analyses can be targeted for future research involving efficient countermeasure design. Our study thus exemplifies the utility of GeneLab data repository to aid in the process of performing novel hypothesis based spaceflight research aimed at elucidating the global impact of environmental stressors at multiple biological scales.

GeneLab↗
NASA NTRS2017

Systemic Microgravity Response: Utilizing GeneLab to Develop Hypotheses for Spaceflight Risks

Biological risks associated with microgravity are a major concern for long-term space travel. Although determination of risk has been a focus for NASA research, data examining systemic (i.e., multi- or pan-tissue) responses to space flight are sparse. To perform our analysis, we utilized the NASA GeneLab database which is a publicly available repository containing a wide array of omics results from experiments conducted with: i) with different flight conditions (space shuttle (STS) missions vs. International Space Station (ISS); ii) a variety of tissues; and 3) assays that measure epigenetic, transcriptional, and protein expression changes. Meta-analysis of the transcriptomic data from 7 different murine and rat data sets, examining tissues such as liver, kidney, adrenal gland, thymus, mammary gland, skin, and skeletal muscle (soleus, extensor digitorum longus, tibialis anterior, quadriceps, and gastrocnemius) revealed for the first time, the existence of potential master regulators coordinating systemic responses to microgravity in rodents. We identified p53, TGF1 and immune related pathways as the highly prevalent pan-tissue signaling pathways that are affected by microgravity. Some variability in the degree of change in their expression across species, strain and time of flight was also observed. Interestingly, while certain skeletal muscle (gastrocnemius and soleus) exhibited an overall down-regulation of these genes, some other muscle types such as the extensor digitorum longus, tibialis anterior and quadriceps, showed an up-regulated expression, indicative of potential compensatory mechanisms to prevent microgravity-induced atrophy. Key genes isolated by unbiased systems analyses displayed a major overlap between tissue types and flight conditions and established TGF1 to be the most connected gene across all data sets. Finally, a set of microgravity responsive miRNA signature was identified and based on their predicted functional state and subsequent impact on health, a theoretical health risk score was calculated. The genes and miRNAs identified from our analyses can be targeted for future research involving efficient countermeasure design. Our study thus exemplifies the utility of GeneLab data repository to aid in the process of performing novel hypothesis based spaceflight research aimed at elucidating the global impact of environmental stressors at multiple biological scales.

GeneLab↗
NASA NTRS2017

Spaceflight Activates Autophagy Programs and the Proteasome in Mouse Liver

Increased oxidative stress is an unavoidable consequence of exposure to the space environment. Our previous studies showed that mice exposed to space for 13.5 days had decreased glutathione levels, suggesting impairments in oxidative defense. Here we performed unbiased, unsupervised and integrated multi-'omic analysis of metabolomic and transcriptomic datasets from mice flown aboard the Space Shuttle Atlantis. Enrichment analyses of metabolite and gene sets showed significant changes in osmolyte concentrations and pathways related to glycerophospholipid and sphingolipid metabolism, likely consequences of relative dehydration of the spaceflight mice. However, we also found increased enrichment of aminoacyl-tRNA biosynthesis and purine metabolic pathways, concomitant with enrichment of genes associated with autophagy and the ubiquitin-proteasome. When taken together with a down-regulation in NRF2-mediated signaling, our analyses suggest that decreased hepatic oxidative defense may lead to aberrant tRNA post-translational processing, induction of degradation programs and senescence-associated mitochondrial dysfunction in response to the spaceflight environment..

Autophagy↗
NASA NTRS2017

Systemic Microgravity Response: Utilizing GeneLab to Develop Hypotheses for Spaceflight Risks

Biological risks associated with microgravity is a major concern for space travel. Although determination of risk has been a focus for NASA research, data examining systemic (i.e., multi- or pan-tissue) responses to space flight are sparse. The overall goal of our work is to identify potential master regulators responsible for such responses to microgravity conditions. To do this we utilized the NASA GeneLab database which contains a wide array of omics experiments, including data from: 1) different flight conditions (space shuttle (STS) missions vs. International Space Station (ISS); 2) different tissues; and 3) different types of assays that measure epigenetic, transcriptional, and protein expression changes. We have performed meta-analysis identifying potential master regulators involved with systemic responses to microgravity. The analysis used 7 different murine and rat data sets, examining the following tissues: liver, kidney, adrenal gland, thymus, mammary gland, skin, and skeletal muscle (soleus, extensor digitorum longus, tibialis anterior, quadriceps, and gastrocnemius). Using a systems biology approach, we were able to determine that p53 and immune related pathways appear central to pan-tissue microgravity responses. Evidence for a universal response in the form of consistency of change across tissues in regulatory pathways was observed in both STS and ISS experiments with varying durations; while degree of change in expression of these master regulators varied across species and strain, some change in these master regulators was universally observed. Interestingly, certain skeletal muscle (gastrocnemius and soleus) show an overall down-regulation in these genes, while in other types (extensor digitorum longus, tibialis anterior and quadriceps) they are up-regulated, suggesting certain muscle tissues may be compensating for atrophy responses caused by microgravity. Studying these organtissue-specific perturbations in molecular signaling networks, we demonstrate the value of GeneLab in characterizing potential master regulators associated with biological risks for spaceflight.

Microgravity↗
NASA NTRS2018

Genetic Regulation of Bone and Cells by Electromagnetic Stimulation Fields and Uses Thereof

The present invention provides methods to modify the genetic regulation of mammalian tissue, bone, cells or any combination thereof by preferential activation, up-regulation and/or down-regulation. The method comprises steps of tuning the predetermined profiles of one or more time-varying stimulation fields by manipulating the B-Field magnitude, rising slew rate, rise time, falling slew rate, fall time, frequency, wavelength, and duty cycle, and exposing mammalian cells or tissues to one or more tuned time-varying stimulation fields with predetermined profiles. Examples of mammalian cells or tissues are chondrocytes, osteoblasts, osteocytes, osteoclasts, nucleus pulposus, associated tissue, or any combination. The resulted modification on gene regulation of these cells, tissues or bones may promote the retention, repair of and reduction of compromised mammalian cartilage, bone, and associated tissue.

Goodwin, Thomas J.↗