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At least 19 records

In Vitro Disease Model of Microgravity Conditioning on Human Energy Metabolism

NASA and its partners are committed to introducing appropriate new technology to enable learning and living safely beyond the Earth for extended periods of time in a sustainable and possibly indefinite manner. In the responsible acquisition of that goal, life sciences is tasked to tune and advance current medical technology to prepare for human health and wellness in the space environment. The space environment affects the condition and function of biological systems from organ level function to shape of individual organelles. The objective of this paper is to study the effect of microgravity on kinetics of drug metabolism. This fundamental characterization is meaningful to (1) scientific understanding of the response of biology to microgravity and (2) clinical dosing requirements and pharmacological thresholds during long term manned space exploration. Metabolism kinetics of the anti-nausea drug promethazine (PMZ) were determined by an in vitro ground model of 3-dimensional aggregates of human hepatocytes conditioned to weightlessness using a rotating wall bioreactor. The authors observed up-regulated PMZ conversion in model microgravity conditions and attribute this to effect to model microgravity conditioning acting on metabolic mechanisms of the cells. Further work is necessary to determine which particular cellular mechanisms are governing the experimental observations, but the authors conclude kinetics of drug metabolism are responsive to gravitational fields and further study of this sensitivity would improve dosing of pharmaceuticals to persons exposed to a microgravity environment.

Snyder, Jessica↗

Accessing and Utilizing Remote Sensing Data for Vectorborne Infectious Diseases Surveillance and Modeling

Background: The transmission of vectorborne infectious diseases is often influenced by environmental, meteorological and climatic parameters, because the vector life cycle depends on these factors. For example, the geophysical parameters relevant to malaria transmission include precipitation, surface temperature, humidity, elevation, and vegetation type. Because these parameters are routinely measured by satellites, remote sensing is an important technological tool for predicting, preventing, and containing a number of vectorborne infectious diseases, such as malaria, dengue, West Nile virus, etc. Methods: A variety of NASA remote sensing data can be used for modeling vectorborne infectious disease transmission. We will discuss both the well known and less known remote sensing data, including Landsat, AVHRR (Advanced Very High Resolution Radiometer), MODIS (Moderate Resolution Imaging Spectroradiometer), TRMM (Tropical Rainfall Measuring Mission), ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer), EO-1 (Earth Observing One) ALI (Advanced Land Imager), and SIESIP (Seasonal to Interannual Earth Science Information Partner) dataset. Giovanni is a Web-based application developed by the NASA Goddard Earth Sciences Data and Information Services Center. It provides a simple and intuitive way to visualize, analyze, and access vast amounts of Earth science remote sensing data. After remote sensing data is obtained, a variety of techniques, including generalized linear models and artificial intelligence oriented methods, t 3 can be used to model the dependency of disease transmission on these parameters. Results: The processes of accessing, visualizing and utilizing precipitation data using Giovanni, and acquiring other data at additional websites are illustrated. Malaria incidence time series for some parts of Thailand and Indonesia are used to demonstrate that malaria incidences are reasonably well modeled with generalized linear models and artificial intelligence based techniques. Conclusions: Remote sensing data relevant to the transmission of vectorborne infectious diseases can be conveniently accessed at NASA and some other websites. These data are useful for vectorborne infectious disease surveillance and modeling.

Kiang, Richard↗

Studying Host-Pathogen Interactions In 3-D: Organotypic Models For Infectious Disease And Drug Development

Representative, reproducible and high-throughput models of human cells and tissues are critical for a meaningful evaluation of host-pathogen interactions and are an essential component of the research developmental pipeline. The most informative infection models - animals, organ explants and human trials - are not suited for extensive evaluation of pathogenesis mechanisms and screening of candidate drugs. At the other extreme, more cost effective and accessible infection models such as conventional cell culture and static co-culture may not capture physiological and three-dimensional aspects of tissue biology that are important in assessing pathogenesis, and effectiveness and cytotoxicity of therapeutics. Our lab has used innovative bioengineering technology to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo, and we have applied these models to study infectious disease. We have established a variety of different 3-D models that are currently being used in infection studies - including small intestine, colon, lung, placenta, bladder, periodontal ligament, and neuronal models. Published work from our lab has shown that our 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo. By virtue of their physiological relevance, 3-D cell cultures may also hold significant potential as models to provide insight into the neuropathogenesis of HIV infection. Furthermore, the experimental flexibility, reproducibility, cost-efficiency, and high throughput platform afforded by these 3-D models may have important implications for the design and development of drugs with which to effectively treat neurological complications of HIV infection.

Nickerson, Cheryl A.↗

Watching Without Seeing a Tool to Surveil Astronaut Health Outcomes While Maintaining Astronaut Medical Privacy

BACKGROUND The Privacy Act of 1974 regulates the use a nd disclosure of personally identifiable information by US Federal agencies. The Act applies to biographical, financial, a nd other identity-linked information, a s well a s personal health information (PHI). As such, the use of astronaut PHI is limited to authorized personnel for preapproved uses, with data reporting often limited to aggregated information about groups. These limitations on the use a nd reporting of astronaut PHI complicates surveillance efforts, wherein epidemiologists a t the National Aeronautics and Space Administration (NASA)monitor the incidence of targeted health conditions in the astronaut population, or to discover emerging trends of aging and disease. Stratification on one or more covariates –particularly time-period, sex, a nd mission participation –can lead to extremely small datasets such that the reporting of results is potentially attributable to individuals. An additional challenge is the small size of the astronaut population, both in terms of numbers of individuals a s well a s in terms of density of exposure time. Such small datasets yield volatile rate estimates that are difficult to interpret. To a id the epidemiological surveillance efforts, a surveillance tool is required that can (a) satisfy the need for rapid computation of condition-specific incidence and mortality rates; (b) improve the statistical estimates of these estimated rates; and (c) maintain astronaut privacy. Here we describe a nd demonstrate such a tool. METHODS We devised a system that models incidence a nd mortality rates rather than calculating them directly. This ha s the advantage of using all the available data to derive the estimates, lea ding to rates that a re not attributable to any one individual, a nd a re a s numerically stable a s they can be given the extremely limited data. The system models disease endpoints using a Poisson regression model with exposure density (measured in person-years) a s a n offset term. By doing so the model is estimating event counts per person-year, equivalent to modeling the rates directly. It uses a standard (pre-specified)set of covariates; the system does not engage in “model-building” as model parsimony is not the goa l. Instead, it is explicitly recognized that if a covariate is not statistically significant a nd not a confounder then it will likely have very little effect on the estimate of the incidence a nd mortality rates. Users are able to specify the disease endpoint of interest and the covariates over which they would like to stratify. The system then uses the resulting model to compute the estimated rates for the user-chosen configuration of variables as visualizes those either over an age range within a specified time-period, or over time for astronauts with a specified age range. RESULTS The first iteration of the tool computes incidence a nd mortality rates for cardiovascular conditions and cancers. Code ha s been developed to retrieve the appropriate data from the IMPALA analysis platform, compute the models for incidence a nd mortality, a nd then use those models to generate the corresponding rate curves. A companion graphical user interface allows the user to specify the curves and visualize the results. CONCLUSIONS It is important to note that the rapid surveillance tool described here is neither meant to be a definitive assessment of the incidence or mortality of any particular disease or condition in the astronaut population, nor is it meant to be used for research purposes. Rather, it is meant as an early indicator that in-depth investigation may be warranted. By automating a repetitive process and leveraging carefully curated astronaut health outcomes, the tool makes possible a rapid “first look” into known areas of concern, and, if used judiciously, may surface new areas of concern for long-term astronaut health. This work is supported in part by the Translational Research Institute for Space Health (TRISH) through NASA Cooperative Agreement NNX16AO69A.

R J Reynolds↗

An Indirect System Identification Technique for Stable Estimation of Continuous-Time Parameters of the Vestibulo-Ocular Reflex (VOR)

The vestibulo-ocular reflex (VOR) is a well-known dual mode bifurcating system that consists of slow and fast modes associated with nystagmus and saccade, respectively. Estimation of continuous-time parameters of nystagmus and saccade models are known to be sensitive to estimation methodology, noise and sampling rate. The stable and accurate estimation of these parameters are critical for accurate disease modelling, clinical diagnosis, robotic control strategies, mission planning for space exploration and pilot safety, etc. This paper presents a novel indirect system identification method for the estimation of continuous-time parameters of VOR employing standardised least-squares with dual sampling rates in a sparse structure. This approach permits the stable and simultaneous estimation of both nystagmus and saccade data. The efficacy of this approach is demonstrated via simulation of a continuous-time model of VOR with typical parameters found in clinical studies and in the presence of output additive noise.

Kukreja, Sunil L.↗

Exploratory Study for Continuous-time Parameter Estimation of Ankle Dynamics

Recently, a parallel pathway model to describe ankle dynamics was proposed. This model provides a relationship between ankle angle and net ankle torque as the sum of a linear and nonlinear contribution. A technique to identify parameters of this model in discrete-time has been developed. However, these parameters are a nonlinear combination of the continuous-time physiology, making insight into the underlying physiology impossible. The stable and accurate estimation of continuous-time parameters is critical for accurate disease modeling, clinical diagnosis, robotic control strategies, development of optimal exercise protocols for longterm space exploration, sports medicine, etc. This paper explores the development of a system identification technique to estimate the continuous-time parameters of ankle dynamics. The effectiveness of this approach is assessed via simulation of a continuous-time model of ankle dynamics with typical parameters found in clinical studies. The results show that although this technique improves estimates, it does not provide robust estimates of continuous-time parameters of ankle dynamics. Due to this we conclude that alternative modeling strategies and more advanced estimation techniques be considered for future work.

neuromuscular systems↗

2014 Space Radiation Standing Review Panel

The 2014 Space Radiation Standing Review Panel (from here on referred to as the SRP) participated in a WebEx/teleconference with members of the Space Radiation Program Element, representatives from the Human Research Program (HRP), the National Space Biomedical Research Institute (NSBRI), and NASA Headquarters on November 21, 2014 (list of participants is in Section XI of this report). The SRP reviewed the updated Research Plan for the Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure (Degen Risk). The SRP also received a status update on the Risk of Acute and Late Central Nervous System Effects from Radiation Exposure (CNS Risk), the Risk of Acute Radiation Syndromes Due to Solar Particle Events (ARS Risk), and the Risk of Radiation Carcinogenesis (Cancer Risk). The SRP thought the teleconference was very informative and that the Space Radiation Program Element did a great job of outlining where the Element is with respect to our state of knowledge on the risks of carcinogenesis, central nervous system effects, and the risk of cardiovascular disease and other degenerative tissue effects from exposure to space radiation. The SRP was impressed with the quality of research that is being conducted and the progress the Space Radiation Program Element has made in the past year. While much work has been done, the SRP had a few remaining questions regarding the broad applicability of these findings to a manned deep space mission (in terms of cognitive function, the paradigms were still hippocampal based and also using Alzheimer disease models). The SRP believes that NASA should consider developing an approach to follow astronauts long-term (beyond retirement) for potential side-effects/risks of space exposure that may be unknown. Radiation toxicities often occur decades after exposure, and potential consequences would be missed if intensified exams stop after retirement of the astronauts. In addition, while cancer is one consequence of radiation exposure that is monitored, potential other side effects (CNS, Alzheimer Disease, loss of cognitive function, etc.) are not included in long-term studies and would be missed. Inclusion of long-term data would be of benefit to the astronauts themselves who have given their service to the corps but also to future astronauts and the future of space exploration.

Steinberg, Susan↗

Cell Culture in Microgravity: Opening the Door to Space Cell Biology

Adaptational response of human cell populations to microgravity is investigated using simulation, short-term Shuttle experiments, and long-term microgravity. Simulation consists of a clinostatically-rotated cell culture system. The system is a horizontally-rotated cylinder completely filled with culture medium. Low speed rotation results in continuous-fall of the cells through the fluid medium. In this setting, cells: 1) aggregate, 2) propagate in three dimensions, 3) synthesize matrix, 4) differentiate, and 5) form sinusoids that facilitate mass transfer. Space cell culture is conducted in flight bioreactors and in static incubators. Cells grown in microgravity are: bovine cartilage, promyelocytic leukemia, kidney proximal tubule cells, adrenal medulla, breast and colon cancer, and endothelium. Cells were cultured in space to test specific hypotheses. Cartilage cells were used to determine structural differences in cartilage grown in space compared to ground-based bioreactors. Results from a 130-day experiment on Mir revealed that cartilage grown in space was substantially more compressible due to insufficient glycosaminoglycan in the matrix. Interestingly, earth-grown cartilage conformed better to the dimensions of the scaffolding material, while the Mir specimens were spherical. The other cell populations are currently being analyzed for cell surface properties, gene expression, and differentiation. Results suggest that some cells spontaneously differentiate in microgravity. Additionally, vast changes in gene expression may occur in response to microgravity. In conclusion, the transition to microgravity may constitute a physical perturbation in cells resulting in unique gene expressions, the consequences of which may be useful in tissue engineering, disease modeling, and space cell biology.

Pellis, Neal R.↗

NASA Classroom Bioreactor

Exploration of space provides a compelling need for cell-based research into the basic mechanisms that underlie the profound changes that occur in terrestrial life that is transitioned to low gravity environments. Toward that end, NASA developed a rotating bioreactor in which cells are cultured while continuously suspended in a cylinder in which the culture medium rotates with the cylinder. The randomization of the gravity vector accomplished by the continuous rotation, in a low shear environment, provides an analog of microgravity. Because cultures grown in bioreactors develop structures and functions that are much closer to those exhibited by native tissue than can be achieved with traditional culture methods, bioreactors have contributed substantially to advancing research in the fields of cancer, diabetes, infectious disease modeling for vaccine production, drug efficacy, and tissue engineering. NASA has developed a Classroom Bioreactor (CB) that is built from parts that are easily obtained and assembled, user-friendly and versatile. It can be easily used in simple school settings to examine the effect cultures of seeds or cells. An educational brief provides assembly instructions and lesson plans that describes activities in science, math and technology that explore free fall, microgravity, orbits, bioreactors, structure-function relationships and the scientific method.

Scully, Robert↗

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.↗

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↗

Biomedical Science and Technology on the International Space Station - Benefits for Humanity (Ciencia Y Tecnologia Biomedica En La Estacion Espacial Internacional - Beneficios Para La Humanidad)

The International Space Station is a unique laboratory for performing investigations that affect human health both in space and on Earth. During its time in orbit, the space station has enabled research that is providing a better understanding of many aspects of human health including aging, trauma, disease and environmental impacts. Driven by the need to support astronaut health, several biological and human physiological investigations have yielded important results that we on Earth can also benefit from. These results include new ways to mitigate bone loss, insights into bacterial behavior, and innovative wound-healing techniques. Advances in telemedicine, disease models, psychological stress response systems, nutrition and cell behavior are just a few more examples of the benefits that have been gained from applying studies in orbit to human health back on Earth.

Love, John E.↗

Biofabrication in Space - A Perspective

Human exploration of Mars is one of the primary goals of NASA. A three-year human exploration mission to Mars is a viable design reference mission (Design Reference Mission). If we are sending a four member crew, comprehensive understanding of the health conditions of the crew is important. Based on the biomedical results of long-duration crew members at ISS, and during gravitational transitions, a few maladaptation have been observed. Discovering the root-cause of these aberrations and finding suitable mitigations at the molecular and cellular levels are of importance for a successful mission. Developing and executing the technologies to carry out tissue generation in space as well as the development of an analog hardware for tissue generation under terrestrial conditions will be discussed. These tissues were typically used to develop disease models and drug toxicology studies for several weeks and many other applications. The significant progress made during the last two decades have unfolded developments in organ generation, stem cell generation in space. When you remove the gravitational force during these cellular building processes while in space, other forces like surface tension, intermolecular forces, Coriolis force, loss of convection, reduced shear force, dominate the environment leading to behavior that we may not observe under terrestrial conditions. Based on these discoveries, the fundamental mechanisms could be better understood and new insights into bioprocesses could be developed for an exciting future.

Antony Jeevarajan↗

Three-Dimensional Cell Culture Models for Infectious Disease and Drug Development

Three-dimensional (3-D) cell cultures hold enormous potential to advance our understanding of infectious disease and to effectively translate basic cellular research into clinical applications. Using novel NASA bioreactor technology, the rotating wall vessel (RWV), we have engineered physiologically relevant 3-D human tissue culture models for infectious disease studies. The design of the RWV is based on the understanding that organs and tissues function in a 3-D environment, and that this 3-D architecture is critical for the differentiated form and function of tissues in vivo. The RWV provides large numbers of cells which are amenable to a wide variety of experimental manipulations and provides an easy, reproducible, and cost-effective approach to enhance differentiated features of cell culture models.

Nickerson, Cheryl A.↗

Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.

NASA Discipline Cell Biology↗

Cardiovascular Disease Spaceflight Equivalent Stressor Risk Modeling Project

The risk of cardiovascular disease (CVD) may be exacerbated by spaceflight hazards including radiation, isolation, distance from the Earth, gravity fields, and closed or confined environments. This project aims to use epidemiologic, scientific research evidence of surrogate spaceflight stressors on analog populations in terrestrial cohorts to model CVD risk for spaceflight conditions. To date, Dr. Butler and the multi-disciplinary CVD Spaceflight Equivalent Stressors (SES) team have conducted a formal systematic literature review on the risk of sleep loss as it relates to cardiovascular disease outcomes and are currently working on a meta-analysis for the data gathered from nearly 100 studies and their various CVD outcomes. The research will continue to examine other surrogate stressors in depth, such as altered gravity, radiation exposure, noise, etc. with cardiovascular outcomes to determine an overall combined spaceflight risk for long term future missions such as Artemis Lunar and Mars missions.

Jennifer Butler↗

Biophysics Representation of the Two-Hit Model of Alzheimer's Disease for the Exploration of Late CNS Risks from Space Radiation

A concern for long-term space travel outside the Earth s magnetic field is the late effects to the central nervous system (CNS) from galactic cosmic ray (GCR) or solar particle events (SPE). Human epidemiology data is severely limited for making CNS risk estimates and it is not clear such effects occur following low LET exposures. We are developing systems biology models based on biological information on specific diseases, and experimental data for proton and heavy ion radiation. A two-hit model of Alzheimer s disease (AD) has been proposed by Zhu et al.(1), which is the framework of our model. Of importance is that over 50% of the US population over the age of 75-y have mild to severe forms of AD. Therefore we recommend that risk assessment for a potential AD risk from space radiation should focus on the projection of an earlier age of onset of AD and the prevention of this possible acceleration through countermeasures. In the two-hit model, oxidative stress and aberrant cell cycle-related abnormalities leading to amyloid-beta plaques and neurofibrillary tangles are necessary and invariant steps in AD. We have formulated a stochastic cell kinetics model of the two-hit AD model. In our model a population of neuronal cells is allowed to undergo renewal through neurogenesis and is susceptible to oxidative stress or cell cycle abnormalities with age-specific accumulation of damage. Baseline rates are fitted to AD population data for specific ages, gender, and for persons with an apolipoprotein 4 allele. We then explore how low LET or heavy ions may increase either of the two-hits or neurogenesis either through persistent oxidative stress, direct mutation, or through changes to the micro-environment, and suggest possible ways to develop accurate quantitative estimates of these processes for predicting AD risks following long-term space travel.

Cucinotta, Francis A.↗