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NASA NTRS2016

Rodent Habitat on ISS: Advances in Capability for Determining Spaceflight Effects on Mammalian Physiology

Rodent research is a valuable essential tool for advancing biomedical discoveries in life sciences on Earth and in space. The National Research Counsel's Decadal survey (1) emphasized the importance of expanding NASAs life sciences research to perform long duration, rodent experiments on the International Space Station (ISS). To accomplish this objective, new flight hardware, operations, and science capabilities were developed at NASA ARC to support commercial and government-sponsored research. The flight phases of two separate spaceflight missions (Rodent Research-1 and Rodent Research-2) have been completed and new capabilities are in development. The first flight experiments carrying 20 mice were launched on Sept 21, 2014 in an unmanned Dragon Capsule, SpaceX4; Rodent Research-1 was dedicated to achieving both NASA validation and CASIS science objectives, while Rodent Reesearch-2 extended the period on orbit to 60 days. Groundbased control groups (housed in flight hardware or standard cages) were maintained in environmental chambers at Kennedy Space Center. Crewmembers previously trained in animal handling transferred mice from the Transporter into Habitats under simultaneous veterinary supervision by video streaming and were deemed healthy. Health and behavior of all mice on the ISS was monitored by video feed on a daily basis, and post-flight quantitative analyses of behavior were performed. The 10 mice from RR-1 Validation (16wk old, female C57Bl6/J) ambulated freely and actively throughout the Habitat, relying heavily on their forelimbs for locomotion. The first on-orbit dissections of mice were performed successfully, and high quality RNA (RIN values>9) and liver enzyme activities were obtained, validating the quality of sample recovery. Post-flight sample analysis revealed that body weights of FLT animals did not differ from ground controls (GC) housed in the same hardware, or vivarium controls (VIV) housed in standard cages. Organ weights analyzed post-flight showed that there were no differences between FLT and GC groups in adrenal gland and spleen weights, whereas FLT thymus and liver weights exceeded those of GC. Minimal differences between the control groups (GC and VIV) were observed. In addition, Over 3,000 aliquots collected post-flight from the four groups of mice were deposited into the Ames Life Science Data Archives for the Biospecimen Sharing Program and Genelab project. New capabilities recently developed include DEXA scanning, grip strength tests and male mice. In conclusion, new capability for long duration rodent habitation of group-housed rodents was developed and includes in-flight sample collection, thus avoiding the complication of reentry. Results obtained to date reveal the possibility of striking differences between the effects of short duration vs. long duration spaceflight. This Rodent Research system enables achievement of both basic science and translational research objectives to advance human exploration of space.

Bone Loss↗
NASA NTRS2016

Biomolecular Analysis Capability for Cellular and Omics Research on the International Space Station

International Space Station (ISS) assembly complete ushered a new era focused on utilization of this state-of-the-art orbiting laboratory to advance science and technology research in a wide array of disciplines, with benefits to Earth and space exploration. ISS enabling capability for research in cellular and molecular biology includes equipment for in situ, on-orbit analysis of biomolecules. Applications of this growing capability range from biomedicine and biotechnology to the emerging field of Omics. For example, Biomolecule Sequencer is a space-based miniature DNA sequencer that provides nucleotide sequence data for entire samples, which may be used for purposes such as microorganism identification and astrobiology. It complements the use of WetLab-2 SmartCycler"TradeMark", which extracts RNA and provides real-time quantitative gene expression data analysis from biospecimens sampled or cultured onboard the ISS, for downlink to ground investigators, with applications ranging from clinical tissue evaluation to multigenerational assessment of organismal alterations. And the Genes in Space-1 investigation, aimed at examining epigenetic changes, employs polymerase chain reaction to detect immune system alterations. In addition, an increasing assortment of tools to visualize the subcellular distribution of tagged macromolecules is becoming available onboard the ISS. For instance, the NASA LMM (Light Microscopy Module) is a flexible light microscopy imaging facility that enables imaging of physical and biological microscopic phenomena in microgravity. Another light microscopy system modified for use in space to image life sciences payloads is initially used by the Heart Cells investigation ("Effects of Microgravity on Stem Cell-Derived Cardiomyocytes for Human Cardiovascular Disease Modeling and Drug Discovery"). Also, the JAXA Microscope system can perform remotely controllable light, phase-contrast, and fluorescent observations. And upcoming confocal microscopy capability will allow for optical sectioning of biological tissues to determine microanatomical localization of biomarkers. Furthermore, NASA's geneLAB effort addresses integration of genomic, epigenomic, transcriptomic, proteomic and metabolomic datasets, by applying an innovative open source science platform for multi-investigator high throughput utilization of the ISS. In sum, the expanding ISS capability for analysis of biomolecules is enabling innovative research in a broad spectrum of areas such as cellular and molecular biology, biotechnology, tissue engineering, biomedicine, and Omics, providing manifold benefits for humanity.

Guinart-Ramirez, Y.↗
NASA NTRS2016

Epigenetics Research on the International Space Station

The International Space Station (ISS) is a state-of-the orbiting laboratory focused on advancing science and technology research. Experiments being conducted on the ISS include investigations in the emerging field of Epigenetics. Epigenetics refers to stably heritable changes in gene expression or cellular phenotype (the transcriptional potential of a cell) resulting from changes in a chromosome without alterations to the underlying DNA nucleotide sequence (the genetic code), which are caused by external or environmental factors, such as spaceflight microgravity. Molecular mechanisms associated with epigenetic alterations regulating gene expression patterns include covalent chemical modifications of DNA (e.g., methylation) or histone proteins (e.g., acetylation, phorphorylation, or ubiquitination). For example, Epigenetics ("Epigenetics in Spaceflown C. elegans") is a recent JAXA investigation examining whether adaptations to microgravity transmit from one cell generation to another without changing the basic DNA of the organism. Mouse Epigenetics ("Transcriptome Analysis and Germ-Cell Development Analysis of Mice in Space") investigates molecular alterations in organ-specific gene expression patterns and epigenetic modifications, and analyzes murine germ cell development during long term spaceflight, as well as assessing changes in offspring DNA. NASA's first foray into human Omics research, the Twins Study ("Differential effects of homozygous twin astronauts associated with differences in exposure to spaceflight factors"), includes investigations evaluating differential epigenetic effects via comprehensive whole genome analysis, the landscape of DNA and RNA methylation, and biomolecular changes by means of longitudinal integrated multi-omics research. And the inaugural Genes in Space student challenge experiment (Genes in Space-1) is aimed at understanding how epigenetics plays a role in immune system dysregulation by assaying DNA methylation in immune cells directly in space using miniPCR technology. In addition, NASA's geneLAB campaign covers the epigenome as part of the "expressome", by employing an innovative open source science platform for multi-investigator high throughput utilization of the ISS. Earth benefits of Epigenetics research onboard the ISS range from contributions to the fundamental understanding of epigenetic phenomena with applications in countermeasure development for biomedical conditions, to the generation of integrated strategies for personalized medicine based on unique physiological responses.

Love, John↗
NASA NTRS2016

Microarray Data Analysis of Space Grown Arabidopsis Leaves for Genes Important in Vascular Patterning

Venation patterning in leaves is a major determinant of photosynthesis efficiency because of its dependency on vascular transport of photo-assimilates, water, and minerals. Arabidopsis thaliana grown in microgravity show delayed growth and leaf maturation. Gene expression data from the roots, hypocotyl, and leaves of A. thaliana grown during spaceflight vs. ground control analyzed by Affymetrix microarray are available through NASA's GeneLab (GLDS-7). We analyzed the data for differential expression of genes in leaves resulting from the effects of spaceflight on vascular patterning. Two genes were found by preliminary analysis to be up-regulated during spaceflight that may be related to vascular formation. The genes are responsible for coding an ARGOS (Auxin-Regulated Gene Involved in Organ Size)-like protein (potentially affecting cell elongation in the leaves), and an F-box/kelch-repeat protein (possibly contributing to protoxylem specification). Further analysis that will focus on raw data quality assessment and a moderated t-test may further confirm up-regulation of the two genes and/or identify other gene candidates. Plants defective in these genes will then be assessed for phenotype by the mapping and quantification of leaf vascular patterning by NASA's VESsel GENeration (VESGEN) software to model specific vascular differences of plants grown in spaceflight.

venation↗
NASA NTRS2016

Microarray Data Analysis of Space Grown Arabidopsis Leaves for Genes Important in Vascular Patterning

Venation patterning in leaves is a major determinant of photosynthesis efficiency because of its dependency on vascular transport of photoassimilates, water, and minerals. Arabidopsis thaliana grown in microgravity show delayed growth and leaf maturation. Gene expression data from the roots, hypocotyl, and leaves of A. thaliana grown during spaceflight vs. ground control analyzed by Affymetrix microarray are available through NASAs GeneLab (GLDS-7). We analyzed the data for differential expression of genes in leaves resulting from the effects of spaceflight on vascular patterning. Two genes were found by preliminary analysis to be upregulated during spaceflight that may be related to vascular formation. The genes are responsible for coding an ARGOS like protein (potentially affecting cell elongation in the leaves), and an F-boxkelch-repeat protein (possibly contributing to protoxylem specification). Further analysis that will focus on raw data quality assessment and a moderated t-test may further confirm upregulation of the two genes and/or identify other gene candidates. Plants defective in these genes will then be assessed for phenotype by the mapping and quantification of leaf vascular patterning by NASAs VESsel GENeration (VESGEN) software to model specific vascular differences of plants grown in spaceflight.

Weitzeal, A. J.↗
NASA NTRS2016

Microarray Data Analysis of Space Grown Arabidopsis Leaves for Genes Important in Vascular Patterning

Venation patterning in leaves is a major determinant of photosynthesis efficiency because of its dependency on vascular transport of photoassimilates, water, and minerals. Arabidopsis thaliana grown in microgravity show delayed growth and leaf maturation. Gene expression data from the roots, hypocotyl, and leaves of A. thaliana grown during spaceflight vs. ground control analyzed by Affymetrix microarray are available through NASA's GeneLab (GLDS-7). We analyzed the data for differential expression of genes in leaves resulting from the effects of spaceflight on vascular patterning. Two genes were found by preliminary analysis to be upregulated during spaceflight that may be related to vascular formation. The genes are responsible for coding an ARGOS like protein (potentially affecting cell elongation in the leaves), and an F-box/kelch-repeat protein (possibly contributing to protoxylem specification). Further analysis that will focus on raw data quality assessment and a moderated t-test may further confirm upregulation of the two genes and/or identify other gene candidates. Plants defective in these genes will then be assessed for phenotype by the mapping and quantification of leaf vascular patterning by NASA's VESsel GENeration (VESGEN) software to model specific vascular differences of plants grown in spaceflight.

Weitzeal, A. J.↗
NASA NTRS2017

Benefits of International Collaboration on the International Space Station

The International Space Station is a valuable platform for research in space, but the benefits are limited if research is only conducted by individual countries. Through the efforts of the ISS Program Science Forum, international science working groups, and interagency cooperation, international collaboration on the ISS has expanded as ISS utilization has matured. Members of science teams benefit from working with counterparts in other countries. Scientists and institutions bring years of experience and specialized expertise to collaborative investigations, leading to new perspectives and approaches to scientific challenges. Combining new ideas and historical results brings synergy and improved peer-reviewed scientific methods and results. World-class research facilities can be expensive and logistically complicated, jeopardizing their full utilization. Experiments that would be prohibitively expensive for a single country can be achieved through contributions of resources from two or more countries, such as crew time, up- and down mass, and experiment hardware. Cooperation also avoids duplication of experiments and hardware among agencies. Biomedical experiments can be completed earlier if astronauts or cosmonauts from multiple agencies participate. Countries responding to natural disasters benefit from ISS imagery assets, even if the country has no space agency of its own. Students around the world participate in ISS educational opportunities, and work with students in other countries, through open curriculum packages and through international competitions. Even experiments conducted by a single country can benefit scientists around the world, through specimen sharing programs and publicly accessible "open data" repositories. For ISS data, these repositories include GeneLab, the Physical Science Informatics System, and different Earth data systems. Scientists can conduct new research using ISS data without having to launch and execute their own experiments. Multilateral collections of research results publications, maintained by the ISS international partnership and accessible via nasa.gov, make ISS results available worldwide, and encourage new users, ideas and research.

Hasbrook, Pete↗
NASA NTRS2017

Benefits of International Collaboration on the International Space Station

The International Space Station is a valuable platform for research in space, but the benefits are limited if research is only conducted by individual countries. Through the efforts of the ISS Program Science Forum, international science working groups, and interagency cooperation, international collaboration on the ISS has expanded as ISS utilization has matured. Members of science teams benefit from working with counterparts in other countries. Scientists and institutions bring years of experience and specialized expertise to collaborative investigations, leading to new perspectives and approaches to scientific challenges. Combining new ideas and historical results brings synergy and improved peer-reviewed scientific methods and results. World-class research facilities can be expensive and logistically complicated, jeopardizing their full utilization. Experiments that would be prohibitively expensive for a single country can be achieved through contributions of resources from two or more countries, such as crew time, up- and downmass, and experiment hardware. Cooperation also avoids duplication of experiments and hardware among agencies. Biomedical experiments can be completed earlier if astronauts or cosmonauts from multiple agencies participate. Countries responding to natural disasters benefit from ISS imagery assets, even if the country has no space agency of its own. Students around the world participate in ISS educational opportunities, and work with students in other countries, through open curriculum packages and through international competitions. Even experiments conducted by a single country can benefit scientists around the world, through specimen sharing programs and publicly accessible "open data" repositories. For ISS data, these repositories include GeneLab and the Physical Science Informatics System. Scientists can conduct new research using ISS data without having to launch and execute their own experiments. Multilateral collections of research results publications, maintained by the ISS international partnership and accessible via nasa.gov, make ISS results available worldwide, and encourage new users, ideas and research. The paper explores international collaboration history, its evolution and maturation, change of focus during its different phases, and growth of its effectiveness (in accordance with the especially established criteria) in the light of benefits for the entire ISS community. With the International Space Station extended through at least 2024, more crew time becoming available and new facilities arriving on board the ISS, these benefits of international scientific collaboration on the ISS can only increase.

Hasbrook, Pete↗
NASA NTRS2017

Benefits of International Collaboration on the International Space Station

The International Space Station is a valuable platform for research in space, but the benefits are limited if research is only conducted by individual countries. Through the e orts of the ISS Program Science Forum, international science working groups, and interagency cooperation, international collaboration on the ISS has expanded as ISS utilization has matured. Members of science teams benefit from working with counterparts in other countries. Scientists and institutions bring years of experience and specialized expertise to collaborative investigations, leading to new perspectives and approaches to scientific challenges. Combining new ideas and historical results brings synergy and improved peer-reviewed scientific methods and results. World-class research facilities can be expensive and logistically complicated, jeopardizing their full utilization. Experiments that would be prohibitively expensive for a single country can be achieved through contributions of resources from two or more countries, such as crew time, up- and downmass, and experiment hardware. Cooperation also avoids duplication of experiments and hardware among agencies. Biomedical experiments can be completed earlier if astronauts or cosmonauts from multiple agencies participate. Countries responding to natural disasters benefit from ISS imagery assets, even if the country has no space agency of its own. Students around the world participate in ISS educational opportunities, and work with students in other countries, through open curriculum packages and through international competitions. Even experiments conducted by a single country can benefit scientists around the world, through specimen sharing programs and publicly accessible \open data" repositories. For ISS data, these repositories include GeneLab, the Physical Science Informatics System, and different Earth science data systems. Scientists can conduct new research using ISS data without having to launch and execute their own experiments. Multilateral collections of research results publications, maintained by the ISS international partnership and accessible via nasa.gov, make ISS results available worldwide, and encourage new users, ideas and research. The paper explores effectiveness of international collaboration in the course of the ISS Program execution. The collaboration history, its evolution and maturation, change of focus during its different phases, and growth of its effectiveness (in accordance with the especially established criteria) are also considered in the paper in the light of benefits for the entire ISS community. With the International Space Station extended through at least 2024, more crew time becoming available and new facilities arriving on board the ISS, these benefits of international scientific collaboration on the ISS can only increase.

Robinson, Julie A.↗
NASA NTRS2017

Machine Learning Approaches to Increasing Value of Spaceflight Omics Databases

The number of spaceflight bioscience mission opportunities is too small to allow all relevant biological and environmental parameters to be experimentally identified. Simulated spaceflight experiments in ground-based facilities (GBFs), such as clinostats, are each suitable only for particular investigations -- a rotating-wall vessel may be 'simulated microgravity' for cell differentiation (hours), but not DNA repair (seconds) -- and introduce confounding stimuli, such as motor vibration and fluid shear effects. This uncertainty over which biological mechanisms respond to a given form of simulated space radiation or gravity, as well as its side effects, limits our ability to baseline spaceflight data and validate mission science. Machine learning techniques autonomously identify relevant and interdependent factors in a data set given the set of desired metrics to be evaluated: to automatically identify related studies, compare data from related studies, or determine linkages between types of data in the same study. System-of-systems (SoS) machine learning models have the ability to deal with both sparse and heterogeneous data, such as that provided by the small and diverse number of space biosciences flight missions; however, they require appropriate user-defined metrics for any given data set. Although machine learning in bioinformatics is rapidly expanding, the need to combine spaceflight/GBF mission parameters with omics data is unique. This work characterizes the basic requirements for implementing the SoS approach through the System Map (SM) technique, a composite of a dynamic Bayesian network and Gaussian mixture model, in real-world repositories such as the GeneLab Data System and Life Sciences Data Archive. The three primary steps are metadata management for experimental description using open-source ontologies, defining similarity and consistency metrics, and generating testing and validation data sets. Such approaches to spaceflight and GBF omics data may soon enable unique insight into which measured phenomena correlate to biological mechanisms that are truly affected by spaceflight conditions; which are most likely to be confounded by other variables; and which are insufficiently characterized, significantly increasing existing and future science return from ISS and spaceflight missions.

Gentry, Diana↗
NASA NTRS2017

Network Analysis of Rodent Transcriptomes in Spaceflight

Network analysis methods leverage prior knowledge of cellular systems and the statistical and conceptual relationships between analyte measurements to determine gene connectivity. Correlation and conditional metrics are used to infer a network topology and provide a systems-level context for cellular responses. Integration across multiple experimental conditions and omics domains can reveal the regulatory mechanisms that underlie gene expression. GeneLab has assembled rich multi-omic (transcriptomics, proteomics, epigenomics, and epitranscriptomics) datasets for multiple murine tissues from the Rodent Research 1 (RR-1) experiment. RR-1 assesses the impact of 37 days of spaceflight on gene expression across a variety of tissue types, such as adrenal glands, quadriceps, gastrocnemius, tibalius anterior, extensor digitorum longus, soleus, eye, and kidney. Network analysis is particularly useful for RR-1 -omics datasets because it reinforces subtle relationships that may be overlooked in isolated analyses and subdues confounding factors. Our objective is to use network analysis to determine potential target nodes for therapeutic intervention and identify similarities with existing disease models. Multiple network algorithms are used for a higher confidence consensus.

genomics↗
NASA NTRS2017

New Developments in NASA's Rodent Research Hardware for Conducting Long Duration Biomedical and Basic Research in Space

Animal models, particularly rodents, are the foundation of pre-clinical research to understand human diseases and evaluate new therapeutics, and play a key role in advancing biomedical discoveries both on Earth and in space. The National Research Councils Decadal survey emphasized the importance of expanding NASA's life sciences research to perform long duration, rodent experiments on the International Space Station (ISS) to study effects of the space environment on the musculoskeletal and neurological systems of mice as model organisms of human health and disease, particularly in areas of muscle atrophy, bone loss, and fracture healing. To accomplish this objective, flight hardware, operations, and science capabilities were developed at NASA Ames Research Center (ARC) to enhance science return for both commercial (CASIS) and government-sponsored rodent research. The Rodent Research Project at NASA ARC has pioneered a new research capability on the International Space Station and has progressed toward translating research to the ISS utilizing commercial rockets, collaborating with academia and science industry, while training crewmembers to assist in performing research on orbit. The Rodent Research Habitat provides a living environment for animals on ISS according to standard animal welfare requirements, and daily health checks can be performed using the habitats camera system. Results from these studies contribute to the science community via both the primary investigation and banked samples that are shared in publicly available data repository such as GeneLab. Following each flight, through the Biospecimen Sharing Program (BSP), numerous tissues and thousands of samples will be harvested, and distributed from the Space Life and Physical Sciences (SLPS) to Principal Investigators (PIs) through the Ames Life Science Data Archive (ALSDA). Every completed mission sets a foundation to build and design greater complexity into future research and answer questions about common human diseases. Together, the hardware improvements (enrichment, telemetry sensors, cameras), new capabilities (live animal return), and experience that the Rodent Research team has gained working with principal investigator teams and ISS crew to conduct complex experiments on orbit are expanding capabilities for long duration rodent research on the ISS to achieve both basic science and biomedical research objectives.

Shirazi, Yasaman↗
NASA NTRS2018

FAIRness and Usability for Open-Access Omics Data Systems

Omics data sharing is especially crucial to the biological research community, and the last decade or two has seen a huge rise in collaborative analysis systems, databases, and knowledge bases for omics and other systems biology data. We assessed the "FAIRness" of NASA's GeneLab Data Systems (GLDS) along with four similar kinds of systems in the research omics data domain, using 14 FAIRness metrics. 14 metrics. The range of Pass ratings was 29-79% of the 14 metrics, Partial Pass 0-21%, and Fail 7-50%. The range of overall FAIRness scores was 5-12 (out of 14). The systems we evaluated performed the best in the areas of data findability and accessibility, and worst in the area of data interoperability. We propose two new principles that Big Data systems, in particular, should consider for increasing data accessibility. We relate our experiences implementing semantic integration of omics data from several systems for the federated querying and retrieval functions of the GLDS, given the shortcomings in data interoperability of these systems.

Berrios, Daniel C.↗
NASA NTRS2015

Experimental Design for Pre-Clinical Animal Model Study in Microgravity

The Rodent Research program at NASAs Ames Research Center (ARC) has pioneered a new research capability on the International Space Station in less than four years and has progressed toward translating research to the ISS utilizing commercial rockets, collaborating with academia and science industry, and training crew for research purposes on-orbit. Animal models are the foundation of pre-clinical research to understand human diseases and evaluate new therapeutics. Advancement in alleviating ground diseases such as muscle atrophy and osteoporosis can come from the study of similar conditions that are known to occur as a result of exposure to the spaceflight environment. During the completion of the flight phase of two missions, our practices, hardware and operations evolved from tested to developed standards, which successfully translated the studies from ground to space. Results from these studies contribute to the science community via both the primary investigation and banked samples that are shared in publicly available data repository such as GeneLab. Every completed mission sets a foundation to build and design greater complexity into future research and answer questions about common human diseases on ground and in space. Here, we present methods developed for the translation of a rodent experiment to the ISS including a description of hardware and kits available for investigators and a discussion of operational constraints.

Rodent Research↗
NASA NTRS2018

FAIRness and Usability for Open-access Omics Data Systems

Omics data sharing is crucial to the biological research community, and the last decade or two has seen a huge rise in collaborative analysis systems, databases, and knowledge bases for omics and other systems biology data. We assessed the "FAIRness" of NASA's GeneLab Data Systems (GLDS) along with four similar kinds of systems in the research omics data domain, using 14 FAIRness metrics. The range of overall FAIRness scores was 6-12 (out of 14), average 10.1, and standard deviation 2.4. The range of Pass ratings for the metrics was 29-79%, Partial Pass 0-21%, and Fail 7-50%. The systems we evaluated performed the best in the areas of data findability and accessibility, and worst in the area of data interoperability. Reusability of metadata, in particular, was frequently not well supported. We relate our experiences implementing semantic integration of omics data from some of the assessed systems for federated querying and retrieval functions, given their shortcomings in data interoperability. Finally, we propose two new principles that Big Data system developers, in particular, should consider for maximizing data accessibility.

Berrios, Daniel C.↗
NASA NTRS2019

Systemic Alterations with Spaceflight Associated Health Risks Originating from Both Circulating miRNAs and Mitochondrial Biology

The many known health risks currently associated with space travel include increased risk of cardiovascular disease, cancer, central nervous system related diseases, muscle degeneration, and changes with host-gut microbiome interactions that can have profound impact with these and other health risks. The majority of the risk from space travel stem of the two components of the space environment which are microgravity and radiation. Two specific systemic effects have been uncovered by us to impact the body as a whole due to the space environment. One factor is related from our earlier work (Beheshti et al, PLOS One, 2018), we predicted that there is a systemic component of the host that causes general increased health risks due to spaceflight driven by a circulating microRNA (miRNA) signature consisting of 13 miRNAs that directly regulates both p53 and TGF1. MiRNAs are small non-coding RNA molecules with a negative and post-transcriptional regulation on gene expression) are increasingly recognized as major systemic regulators of responses to stressors, including microgravity, oxidative stress, and DNA damage. In addition, due to the size and stability of miRNAs, it is known that miRNAs can circulate throughout the body and have been found in the majority of the bodily fluids including blood, urine, saliva, and tears. Here, we start to dissect the actual impact of this miRNA signature on both the radiation and microgravity components and prove that this miRNA signature actually exists in the circulation of a host. The other systemic factor we uncovered was the impact the mitochondria on the whole body due to spaceflight. We hypothesize that spaceflight may promote a physiologic response driven by systemic mitochondria pathways leading to metabolic disorder stemming from the liver and directly impacting other organs and tissues. A systems biology method was implemented utilizing GeneLab datasets that involved in vitro experiments performed at the low Earth orbit, in vivo experiments involving mice flown to space, and finally human physiological data from astronauts. A comprehensive multi-omics approach was implemented which involved correlating transcriptomic analysis with proteomics, metabolomics, and methylation analysis. This approach led us to confirm our hypothesis that a systemic mitochondrial driven response is responsible for increasing potential health risk and is conserved from the in vitro studies, to the in vivo studies, and finally confirmed in astronauts.

Radiation↗
NASA NTRS2018

Transcriptomics and Proteomics Discussion

This presentation will cover the the basic pipelines for transcriptomics and proteomics that the GeneLab Analysis Working Groups (AWGs) have so far determined to be optimal. Basic transcriptomic pipelines will first be presented from primary analysis to higher-order systems analysis. Examples of how the data has been analyzed will be presented. Proteomics pipelines will also be presented compiled from various AWG members. Discussion will be generated from the AWG members to reach a consensus for each omic type.

Transcriptomics↗
NASA NTRS2019

A Multi-Omics Approach Demonstrates that Spaceflight Leads to Lipid Accumulation in Mouse Livers

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models. We analyzed liver transcriptomic and proteomic data from three mouse spaceflight experiments flown aboard the International Space Station (Rodent Research-1 NASA (RR-1 NASA), Rodent Research-1 CASIS (RR-1 CASIS), Rodent Research-3 (RR-3)), and one mouse experiment flown on the Space Shuttle (Commercial Biomedical Testing Module-3 (CBTM-3) aboard STS-135). Despite the differences in genetic background and time of exposure to microgravity it was shown through Oil Red staining and histology that increased lipid accumulation was occurring in the liver of all mice flown in space compared to the ground controls. This led to further pursue the existing GeneLab datasets related to liver omics data from these mice. We were able to discover key conserved pathways across all the mice independent of the flight conditions that were related to increased lipid metabolism, fatty acid metabolism, both lipid and fatty acid processing, lipid catabolic processing, and lipid localization. In addition, key upstream regulators were predicted to be commonly regulated across all conditions which include ESR1, GCG, and NR1I2 being inhibited and INS being activated. Interestingly, estrogen receptor alpha (ESR1) expression has been known to be heavily involved with lipoprotein metabolism. In addition, insulin (INS) is the primary driver for fat metabolism and increased INS has been associated with increased fatty acids in the liver. Through additional proteomic analysis we were able to identify the majority of the key proteins related to lipids for both the RR-1 and RR-3 rodents were being up-regulated in the livers when comparing flight to ground controls. This additional confirmation of the lipid associated activity also showed that the lipid related proteins are heavily involved with lipid metabolism, cholesterol binding, and cholesterol metabolism. Lastly, the analysis also revealed that the circadian clock related pathways in the liver are commonly being increased across all space flight conditions which has also been reported in the literature to potentially cause increased liver damage. The combination of the very strong lipid uptake in the liver and the transcriptomic/proteomic signatures (including the circadian clock pathways) following spaceflight are consistent with early onset of liver disease. Taken together, these data indicate that, activation of lipotoxic pathways could persist during longer duration spaceflight which might result in the development of liver disease

Lipids↗