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Beheshti, Afshin

Publications and source records attributed to Beheshti, Afshin.

At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS2020

Circulating miRNA Signature Predicts Health Risks Associated with Cancer and Spaceflight

Biological risks associated with space radiation and microgravity are major concerns for long-term space travel. Through a Systems Biology approach, our previous NASA work has shown both TGF signaling pathways and miRNAs have a critical impact on defining health risks with and without space irradiation. We hypothesize that circulating microRNA (miRNA) signatures are driving microvascular disease and muscle degeneration associated with accelerating aging and will be enhanced by exposure to the space environment (radiation and microgravity). We are investigating this hypothesis with both in vivo and in vitro models to test novel antagonist therapies to these miRNA signatures as countermeasures to reduce space radiation-induced health risks. A comprehensive Systems Biology approach is utilized to examine the influence by high atomic number by high (H) atomic number (Z) and energy (E) (HZE) irradiation. To simulate low-dose exposure due to galactic cosmic rays (GCR), we used ions, energy, and doses determined by a NASA consensus formula of 7 different ions to represent GCR (referred to as GCR sim model). To similate high-dose radiation exposure due to solar particle events (SPE), we used a solar particle event (SPE) sim model which gave a total dose of 1Gy protons with energy ranges from 50MeV to 150MeV. C57BL/6 wild-type female mice were utilized for the irradiations with our established simulated microgravity model (hindlimb suspension model) and an in vitro 3D microvasculature tissue model under simulated microgravity (clinostat) conditions was also irradiated. To expand on the circulating miRNA signature determined from our preliminary data, we determined a group of conserved miRNAs which are commonly being regulated in the majority of the organs and tissues throughout the host using our established techniques. MiRNA-sequencing was done on serum (at time of sacrifice), liver, heart, and muscle (soleus muscle) tissue for all radiation groups. Additional validation of the key miRNAs was performed by droplet digital PCR (ddPCR). This revealed a key circulating miRNA signature (consisting of multiple miRNAs) impacting cardiovascular and muscular disease risk. Further in vitro experiments with CRISPR/Cas9 system to knockout the key miRNA signatures, novel self-delivering antagomirs, overexpression of the miRNAs test the functional impact of the miRNA signatures on both microvascular disease and muscle degeneration due to space irradiation. The current work has started to allow the possible development of a novel minimally invasive miRNA based radioprotector to be used as a countermeasure for space radiation. Collectively, understanding of how whole body space radiation impacts microvascular and tissue degeneration through circulating miRNAs will greatly enhance health risk prognostication and provide possible new mechanisms for protection against space radiation. This work is supported by the Translational Research Institute through NASA Cooperative Agreement NNX16AO69A (T-0404) awarded to AB.

Beheshti, Afshin↗
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↗
NASA NTRS2019

Circulating miRNA Signature Predicts Health Risks Associated with Radiation and Microgravity

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. 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. To achieve this, we obtained multiple tissues including, serum, liver, and spleen and utilizing droplet digital PCR (ddPCR), we start to show how this circulating miRNA signature impacts which component of the spaceflight. The tissue was obtained from experiments performed on C57BL/6 male mice (N=10 for each condition) that were hindlimb unloaded (HU) to simulated microgravity, irradiated with 2Gy gamma (IR), HU plus IR, and control mice under normal conditions. It was shown that these miRNAs were present in the serum as predicted by the in silico prediction from our earlier predictions. The HU vs Controls show significant increases of the predicted miRNAs in the serum for more than half of the miRNA signature, with remaining miRNAs increasing comparing to the controls close to statistical significance. IR vs control mice showed increases for the miRNAs, but not has pronounced as the HU conditions. Finally, the combination of the HU+IR vs controls showed increases for the majority of the miRNA signature. The data indicates that the miRNA signature originally predicted through in silico methods is mainly associated with the microgravity component and is circulating throughout the host resulting in a systemic impact of the miRNAs on the host. These miRNAs are shown in the literature to potentially increase health risks associated with several diseases. In addition, we have begun testing the potential of utilizing antagonists to this miRNA signature to act as a potential countermeasure to mitigate radiation impact on the organism. This work demonstrates for the first time the potential of a minimally invasive novel biomarker and countermeasure that can be used to mitigate both radiation and microgravity effects.

Beheshti, Afshin↗
NASA NTRS2019

Cross Kingdom Analysis of Data Within the GeneLab Repository Identifies a Potential Conserved Response of Life to the Stress Associated with Spaceflight

It is important to determine the health risks and potential survival for astronauts associated with long-term space missions. This entails not only understanding the impact the space environment will have on humans, but also how it will affect other organisms needed for humans to survive in space such as plants. In addition, it has been reported in the literature that hundreds of genes seem to be conserved and/or transferred between different organisms from bacteria, archaea, fungi, microorganisms, and plants to animals. Since space travel involves humans in a closed environment over a long period of time, we hypothesize that potential conserved biological factors will occur between the different organisms in that environment possibly due to transfer of genes. Determining the conserved factors that are commonly being regulated in space can shed insight into possible universal master regulators and also determine the symbiotic relationship between the organisms in space. Utilizing NASA's GeneLab Data Repository (a rapidly expanding, curated clustering of spaceflight-related ‘omics-level datasets for all organisms), we were able to uncover a novel pathway and factors that were commonly shared between humans, mice, plants, C. Elegans, and drosophilas. Through ChIP-Seq enrichment analysis techniques utilizing various GeneLab datasets from each species that were flown in space, we found the following factors to be conserved across all species: oxidative stress, DNA damage (through GABPA/NRFs and NFY), SIX5, GTF2B and glutamine synthetase. Such commonalities would likely reflect the effects of factors such as microgravity and the increased radiation exposure inherent in spaceflight on basic physical processes shared by all biological systems at the cellular level. Differences between organismal responses revealed by GeneLab's data should also help understand the unique reactions to life in space that arise from the very different lifestyles of microbes, animals and plants.

Barker, Richard↗
NASA NTRS2019

Nasa GeneLab Computomics Reveal Horizontal Gene Transfer on International Space Station Environmental Metagenomes

Prokaryotic lifeforms can be observed to demonstrate many keen adaptive advantages, perhaps facilitated by a nature simplistic relative to divergent domains of life. In particular, decompartmentalized gene expression facilitates adaptation by allowing free exchange of genetic material, albeit at the cost of increased susceptibility to genetic damage. Thus, these lifeforms must compensate by embracing diverse investment strategies in an attempt to “brute force” the evolvability equation through precipitous genesis, lean metabolic efficiency, and sheer population. This prokaryotic archetype also enables symbiotic relationships with secondary mobile genetic elements known as plasmids, which have been shown to drive evolution on rapid temporal scales through processes such as conjugation and transformation. This study attempts to decipher whether these mechanisms of horizontal gene transfer (HGT) are major factors in determining prokaryote fitness within a unique isolated environment, the International Space Station (ISS). The ISS Microbial Tracking (MT) project has generated a wealth of data concerning the successive reigns of microbial genera that appear to thrive amidst harsh conditions for life. Despite relatively higher doses of ionizing radiation as compared to Earth, complications associated with microgravity, and the anti-microbial mélange deployed, microbial life still persists in this environment. The NASA GeneLab serves as a data repository and analysis platform to enable researchers to access space flight factor related data. With the use of GeneLab’s modern computational suites (computomics), phylogenetic and functional genomic investigations of HGT events were conducted on the data generated from the MT-1 project. The putative data concerning the plasmid population (plasmidome) of the ISS was algorithmically derived and compared to those of habitats with similar environmental dynamics- such as living quarters and hospitals- to investigate whether these HGT elements may play crucial role(s) in shaping the microbiome of this closed habitat that serves as the only inhabited structure in space.

Bense, Nicholas↗
NASA NTRS2019

NASA GeneLab Platform Utilized for Space Radiation Dosimetry Biological Response Compared to Radiation Ground Studies

Ionizing radiation from Galactic Cosmic Rays (GCR) is one of the major risk factors factor that will impact health of astronauts on extended missions outside the protective effects of the Earth's magnetic field. Currently there are gaps in our knowledge of the health risks associated with chronic low dose, low dose rate ionizing radiation, specifically ions associated with high (H) atomic number (Z) and energy (E). The NASA GeneLab project (genelab.nasa.gov) aims to provide a detailed library of Omics datasets associated with biological samples exposed to HZE. The GeneLab Data System (GLDS) includes datasets from both spaceflight and ground-based studies, a majority of which involved exposure to ionizing radiation. Recently GeneLab has also assessed radiation dosimetry data with omics datasets associated with samples flown to the International Space Station (ISS). The combination of the detailed information on radiation exposure for ground-based studies and curated dosimetry information for spaceflight experiments allows GeneLab to be the first comprehensive Omics database for space related research from which an investigator can generate hypotheses to direct future experiments utilizing both ground and space biological radiation data. We demonstrate the usefulness of these datasets by analyzing multiple GeneLab datasets associated with both radiation ground-based studies and spaceflight studies. The radiation ground based studies we analyzed includes both in vivo and in vitro work with a range ions from protons to iron particles with doses from 0.1Gy to 2Gy. These datasets were compared to both in vivo and in vitro datasets from samples flown to the ISS and on shorter shuttle missions with total doses of 0.1 mGy to 30 mGys. From this analysis we were able to associate distinct biological signatures associating specific ions to specific biological response to radiation exposure in space. For example, we discovered radiation biological response related to cardiovascular effects from proton ground studies are the dominating response for samples related to cardiovascular effects on the ISS. With this work we will provide a summary of how different ions will impact different biological response in space and how this can be used in future studies to assess optimal ground experiments to simulate space radiation.

Beheshti, Afshin↗
NASA NTRS2019

Science Driven By Space Biology Omics Data Utilizing NASA's GeneLab Platform

Determining the biological impact of spaceflight through novel approaches is essential to reduce the health risks to astronauts for long-term space missions. The current established health risks due to spaceflight are only reflecting known symptomatic and physiologic responses and do not reflect early onset of other potential diseases. There are many unknown variables which still need to be identified to fully understand the health impacts due to the environmental factors in space. One method to uncover potential novel biological mechanisms responsible for health risks in astronauts is by utilizing NASA's GeneLab Data Systems (genelab.nasa.gov). GeneLab is public repository that hosts multiple omics datasets generated from space biology experiments that include experiments flown in space, simulated cosmic radiation.

Beheshti, Afshin↗
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

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 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 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 NTRS2018

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

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

Beheshti, Afshin↗
NASA NTRS2018

GeneLab: "Omics" Data Systems for Spaceflight and Simulated Spaceflight Environment

NASA's GeneLab Data System is a repository that hosts multi-omics datasets generated by biological experiments flown onboard the International Space Station. Strategies regarding how GeneLab envisions the involvement of the scientific community and the public at large will be discussed, and current and future capabilities of the system will be described. Information describing how scientists can participate in analyzing the current datasets on plants, microbes, invertebrates or mammals will be provided, and initial findings from the current datasets will be discussed during this presentation. Anyone interested in genomics, transcriptomics, epigenomics and proteomics, and systems biology, or who is curious to understand how space modifies living organisms should attend.

Omics↗
NASA NTRS2018

GeneLab: "Omics" Data Systems for Spaceflight and Simulated Spaceflight Environment

Determining the biological impact of spaceflight through novel approaches is essential to reduce the health risks to astronauts for long-term space missions. The current established health risks due to spaceflight are only reflecting known symptomatic and physiologic responses and do not reflect early onset of other potential diseases. There are many unknown variables which still need to be identified to fully understand the health impacts due to the environmental factors in space. One method to uncover potential novel biological mechanisms responsible for health risks in astronauts is by utilizing NASA's GeneLab Data Systems (genelab.nasa.gov). GeneLab is public repository that hosts multiple omics datasets generated from space biology experiments that include experiments flown in space, simulated cosmic radiation experiments, and simulated microgravity experiments. This presentation will provide an overview of GeneLab and examples of analysis that are being done with GeneLab datasets. These example will include novel data and work being generated with various scientists around the world involved with GeneLab's Analysis Working Groups (AWG) that are assisting with the development of pipelines and advancing GeneLab to the next phase, a publication from GeneLab discovering novel Carbon Dioxide impact due to rodent habitats, another publication from GeneLab discovering a potential master regulator responsible for health risk associated due to spaceflight, and potential cardiovascular risk from space radiation

spaceflight↗
NASA NTRS2018

GeneLab: "Omics" Data System for Space Biology Research

Determining the biological impact of spaceflight through novel approaches is essential to reduce the health risks to astronauts for long-term space missions. The current established health risks due to spaceflight are only reflecting known symptomatic and physiologic responses and do not reflect early onset of other potential diseases. There are many unknown variables which still need to be identified to fully understand the health impacts due to the environmental factors in space. One method to uncover potential novel biological mechanisms responsible for health risks in astronauts is by utilizing NASA's GeneLab Data Systems (genelab.nasa.gov). GeneLab is public repository that hosts multiple omics datasets generated from space biology experiments that include experiments flown in space, simulated cosmic radiation experiments, and simulated microgravity experiments. This presentation will provide an overview of GeneLab and examples of analysis that are being done with GeneLab datasets. These example will include novel data and work being generated with various scientists around the world involved with GeneLab's Analysis Working Groups (AWG) that are assisting with the development of pipelines and advancing GeneLab to the next phase, a publication from GeneLab discovering novel Carbon Dioxide impact due to rodent habitats, another publication from GeneLab discovering a potential master regulator responsible for health risk associated due to spaceflight, and potential cardiovascular risk from space radiation.

microgravity↗