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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
NASA NTRSDate not supplied

Developing High-Throughput Organ-on-a-Chip Models to Investigate the Effects of Ionizing Radiation on the Central Nervous System

One of the main health risks in human space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to the galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neuronal damage and neuroinflammation associated with cognitive and behavioral dysfunction. In general, the extent of CNS damage is partially regulated by the blood-brain barrier (BBB), which enables immune cells to enter the CNS. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, immune responses and oxidative stress, and thus could serve as a robust CNS-specific target for countermeasure development. However, studies on BBB permeability and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we established a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments in response to ionizing radiation, based on commercially available OrganoPlates (Mimetas, Inc.) seeded with primary or induced pluripotent stem cell-derived human cells. We investigated both immediate and delayed CNS responses to major GCR components: 0.15-0.5 Gy 250MeV/n 4-He, and 0.3-0.8 Gy 600 MeV/n 56-Fe; as well as to 0.5-1 Gy X-rays. We observed ionizing radiation-mediated increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by morphological changes in endothelial cells and tight junctions, altered cytokine profile including TNFa upregulation, and increased oxidative stress. We also quantified irradiation-mediated changes in astrocyte activation and neuronal functions, revealing major astrocyte damage mediated by 600MeV/n 56-Fe particles. Thus, we demonstrate that deep space radiation may contribute to CNS damage by disrupting both astrocyte and endothelial cell components of the blood-brain barrier. Our next steps include mapping and validating the transcriptomic changes induced by simulated GCRs and their components in human CNS models. Ultimately, we aim to uncover potential novel targets for countermeasure developments to mitigate CNS damage in long duration spaceflight.

Radiation↗
NASA NTRS2006

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.↗
NASA NTRS1999

Modeling Calcium Loss from Bones During Space Flight

Calcium loss from bones during space flight creates a risk for astronauts who travel into space, and may prohibit space flights to other planets. The problem of calcium loss during space flight has been studied using animal models, bed rest (as a ground-based model), and humans in-flight. In-flight studies have typically documented bone loss by comparing bone mass before and after flight. To identify changes in metabolism leading to bone loss, we have performed kinetic studies using stable isotopes of calcium. Oral (Ca-43) and intravenous (Ca-46) tracers were administered to subjects (n=3), three-times before flight, once in-flight (after 110 days), and three times post-flight (on landing day, and 9 days and 3 months after flight). Samples of blood, saliva, urine, and feces were collected for up to 5 days after isotope administration, and were analyzed for tracer enrichment. Tracer data in tissues were analyzed using a compartmental model for calcium metabolism and the WinSAAM software. The model was used to: account for carryover of tracer between studies, fit data for all studies using the minimal number of changes between studies, and calculate calcium absorption, excretion, bone calcium deposition and bone calcium resorption. Results showed that fractional absorption decreased by 50% during flight and that bone resorption and urinary excretion increased by 50%. Results were supported by changes in biochemical markers of bone metabolism. Inflight bone loss of approximately 250 mg Ca/d resulted from decreased calcium absorption combined with increased bone resorption and excretion. Further studies will assess the time course of these changes during flight, and the effectiveness of countermeasures to mitigate flight-induced bone loss. The overall goal is to enable human travel beyond low-Earth orbit, and to allow for better understanding and treatment of bone diseases on Earth.

Wastney, Meryl E.↗
DOE OSTI2024

Characterization of Histophilus somni sialic acid uptake mutant (Δ nanP -Δ nanU ) using a mouse septicemia and mortality model

Histophilus somni is an important pathogen of the bovine respiratory disease complex, yet the mechanisms underlying its virulence remain poorly understood. It is known that H. somni can incorporate sialic acid into lipooligosaccharide (LOS), and sialylated H. somni is more resistant to phagocytosis and complement-mediated killing by serum compared to non-sialylated bacteria in vitro. However, the virulence of non-sialylated H. somni has not been evaluated in vivo using an animal model. In this study, we investigated the contribution of sialic acid to virulence by constructing an H. somni sialic acid uptake mutant (ΔnanP-ΔnanU) and comparing the parent and mutant strains in a mouse septicemia and mortality model. Intraperitoneal challenge of mice with wildtype H. somni (1 × 10 8 colony forming units/mouse, CFU) was lethal to all animals. Mice challenged with three different doses (1, 2, or 5 × 108 CFU/mouse) of an H. somni ΔnanP-ΔnanU sialic acid uptake mutant exhibited survival rates of 90 %, 60 %, and 0 % respectively. High-performance anion exchange chromatography analyses revealed that LOS prepared from both parent and the ΔnanP-ΔnanU mutant strains of H. somni were sialylated. These findings suggest the presence of de novo sialic acid synthesis pathway, although the genes associated with de novo sialic acid synthesis (neuB and neuC) were not identified by genomic analysis. The lower attenuation in mice is most likely attributed to the sialylated LOS of H. somni nanPU mutant.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2014

Radiation Quality Effects on Transcriptome Profiles in 3-D Cultures After Charged Particle Irradiation

In this work, we evaluated the differential effects of low- and high-LET radiation on 3-D organotypic cultures in order to investigate radiation quality impacts on gene expression and cellular responses. Current risk models for assessment of space radiation-induced cancer have large uncertainties because the models for adverse health effects following radiation exposure are founded on epidemiological analyses of human populations exposed to low-LET radiation. Reducing these uncertainties requires new knowledge on the fundamental differences in biological responses (the so-called radiation quality effects) triggered by heavy ion particle radiation versus low-LET radiation associated with Earth-based exposures. In order to better quantify these radiation quality effects in biological systems, we are utilizing novel 3-D organotypic human tissue models for space radiation research. These models hold promise for risk assessment as they provide a format for study of human cells within a realistic tissue framework, thereby bridging the gap between 2-D monolayer culture and animal models for risk extrapolation to humans. To identify biological pathway signatures unique to heavy ion particle exposure, functional gene set enrichment analysis (GSEA) was used with whole transcriptome profiling. GSEA has been used extensively as a method to garner biological information in a variety of model systems but has not been commonly used to analyze radiation effects. It is a powerful approach for assessing the functional significance of radiation quality-dependent changes from datasets where the changes are subtle but broad, and where single gene based analysis using rankings of fold-change may not reveal important biological information.

Patel, Zarana S.↗
NASA NTRS1989

Late cataractogenesis caused by particulate radiations and photons in long-lived mammalian species

Radiation cataractogenesis induced by small acute doses of particulate radiations and photons in the New Zealand white rabbit (Oryctolagus cuniculus), the beagle dog (Canis familiaris) and the rhesus monkey (Macaca mulatta) is discussed in the context of the use of animal models to assess the radiation hazards faced by humans during lengthy sojourns in deep space. Attention is paid to (1) the importance of lifespan studies with long-lived species - the above animals have median lifespans in captivity of 5-7, 13-14 and 25 years, respectively; and (2) the magnitudes of possible dose thresholds for cataractogenesis from sparsely ionizing radiations and the modifications of those thresholds by the late degenerative phase of the phenomenon.

Lett, J. T.↗
NASA NTRS1996

Telemetric Sensors for the Space Life Sciences

Telemetric sensors for monitoring physiological changes in animal models in space are being developed by NASA's Sensors 2000! program. The sensors measure a variety of physiological measurands, including temperature, biopotentials, pressure, flow, acceleration, and chemical levels, and transmit these signals from the animals to a remote receiver via a wireless link. Thus physiologic information can be obtained continuously and automatically without animal handling, tethers, or percutaneous leads. We report here on NASA's development and testing of advanced wireless sensor systems for space life sciences research.

Hines, John W.↗
NASA NTRS2018

Challenges in Clinical Management of Radiation-Induced Illnesses in Exploration Spaceflight

Historical solar particle events (SPEs) provide context for some understanding of acute radiation exposure risk to astronauts traveling outside of low Earth orbit. Modeling of potential doses delivered to exploration crewmembers anticipates limited radiation-induced health impacts, including prodromal symptoms of nausea, emesis, and fatigue, but suggests that more severe clinical manifestations are unlikely. Recent large animal-model research in space-analogs closely mimicking SPEs has identified coagulopathic events independent of the hematopoietic sequelae of higher radiation doses, similar in manifestation to disseminated intravascular coagulation (DIC). We explored the challenges of clinical management of radiation-related clinical manifestations, using currently accepted modeling techniques and anticipated physiological sequelae, to identify medical capabilities needed to successfully manage SPE-induced radiation illnesses during exploration spaceflight.

Blue, Rebecca↗
NASA NTRS2002

Fluid Mechanics of Capillary-Elastic Instabilities in Microgravity Environment

The aim of this project is to investigate the closure and reopening of lung airways due to surface tension forces, coupled with airway elasticity. Airways are liquid-lined, flexible tubes and closure of airways can occur by a Rayleigh instability of the liquid lining, or an instability of the elastic support for the airway as the surface tension of the air-liquid interface pulls the tube shut, or both. Regardless of the mechanism, the airway is closed because the liquid lining has created a plug that prevents axial gas exchange. In the microgravity environment, surface tension forces dominate lung mechanics and would lead to more prevalent, and more uniformly distributed air-way closure, thereby creating a potential for respiratory problems for astronauts. Once closed the primary option for reopening an airway is by deep inspiration. This maneuver will pull the flexible airways open and force the liquid plug to flow distally by the incoming air stream. Airway reopening depends to a large extent on this plug flow and how it may lead to plug rupture to regain the continuity of gas between the environment and the alveoli. In addition to mathematical modeling of plug flows in liquid-lined, flexible tubes, this work has involved benchtop studies of propagating liquid plugs down tube networks that mimic the human airway tree. We have extended the work to involve animal models of liquid plug propagation in rat lungs. The liquid is radio-opaque and x-ray video imaging is used to ascertain the movement and distribution of the liquid plugs so that comparisons to theory may be made. This research has other uses, such as the delivery of liquids or drugs into the lung that may be used for surfactant replacement therapy or for liquid ventilation.

Grotberg, James B.↗
NASA NTRS2019

Developing High-Throughput Organ-On-A-Chip Models to Investigate the Effects of Ionizing Radiation on the Central Nervous System

One of the main health risks in human space exploration is central nervous system (CNS) damage by ionizing radiation. Irradiation with simulated GCRs or their components, or high doses of low-LET radiation such as gamma rays, in animal models has been shown to cause neuronal damage together with glial cell activation and neuroinflammation and has been associated with prolonged cognitive and behavioral dysfunction. The extent of CNS damage in response to any insult, including ionizing radiation, is partially regulated by the blood-brain barrier (BBB), which enables immune cells to enter the CNS. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, immune responses and oxidative stress, and thus could serve as a robust CNS-specific target for countermeasure development. However, studies on BBB permeability and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we have established a high throughput 3D organ-on-a-chip system to study human CNS functions in response to ionizing radiation, with the eventual goal of adapting it to spaceflight missions. We utilized commercially available OrganoPlate system (Mimetas, Inc.) seeded with primary or induced pluripotent stem cell-derived human cells for developing 3D neuronal-astrocytic and BBB models. We investigated both immediate and delayed CNS dose responses to 0.5-1 Gy X-rays by measuring BBB permeability and morphology, and astrocyte activation. We have also quantified secreted markers of oxidative stress and cell viability. In the future, we are planning to monitor dendritic, axonal and synaptic changes in neurons, evaluate the combined exposures to simulated microgravity and ionizing radiation, and compare the responses to low and high-LET ionizing radiation. We anticipate these studies could indicate novel cellular and mechanistic targets for countermeasure developments to improve CNS functions in astronauts.

Malkani, Sherina↗
NASA NTRS2014

Role of Oxidative Damage in Radiation-Induced Bone Loss

During prolonged spaceflight, astronauts are exposed to both microgravity and space radiation, and are at risk for increased skeletal fragility due to bone loss. Evidence from rodent experiments demonstrates that both microgravity and ionizing radiation can cause bone loss due to increased bone-resorbing osteoclasts and decreased bone-forming osteoblasts, although the underlying molecular mechanisms for these changes are not fully understood. We hypothesized that excess reactive oxidative species (ROS), produced by conditions that simulate spaceflight, alter the tight balance between osteoclast and osteoblast activities, leading to accelerated skeletal remodeling and culminating in bone loss. To test this, we used the MCAT mouse model; these transgenic mice over-express the human catalase gene targeted to mitochondria, the major organelle contributing free radicals. Catalase is an anti-oxidant that converts reactive species, hydrogen peroxide into water and oxygen. This animal model was selected as it displays extended lifespan, reduced cardiovascular disease and reduced central nervous system radio-sensitivity, consistent with elevated anti-oxidant activity conferred by the transgene. We reasoned that mice overexpressing catalase in mitochondria of osteoblast and osteoclast lineage cells would be protected from the bone loss caused by simulated spaceflight. Over-expression of human catalase localized to mitochondria caused various skeletal phenotypic changes compared to WT mice; this includes greater bone length, decreased cortical bone area and moment of inertia, and indications of altered microarchitecture. These findings indicate mitochondrial ROS are important for normal bone-remodeling and skeletal integrity. Catalase over-expression did not fully protect skeletal tissue from structural decrements caused by simulated spaceflight; however there was significant protection in terms of cellular oxidative damage (MDA levels) to the skeletal tissue. Furthermore, we used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

oxidative damage↗
NASA NTRS1983

Thermoneutral zone and scaling of metabolic rate on body mass in small mammals

A 4-species animal model suitable for experimental study of the effect of change in gravitational loading on the scale relationship between metabolic rate and total body mass is used to study the effect of temperature on metabolic rate in six male animals, 8-10 months of age, of each of the four species in the ambient temperature range 20-36 C. The measurements taken permitted partitioning of total body heat output into sensible heat loss by radiation, conduction and convection, and into latent heat loss by evaporation of water from the body surface. It is shown that the condition of thermoneutrality is important for metabolic scale effect studies, and that the thermoneutral zone for the species considered here is a narrow one.

Pace, N.↗
NASA NTRS2012

A Multiscale Computational Model of the Response of Swine Epidermis After Acute Irradiation

Radiation exposure from Solar Particle Events can lead to very high skin dose for astronauts on exploration missions outside the protection of the Earth s magnetic field [1]. Assessing the detrimental effects to human skin under such adverse conditions could be predicted by conducting territorial experiments on animal models. In this study we apply a computational approach to simulate the experimental data of the radiation response of swine epidermis, which is closely similar to human epidermis [2]. Incorporating experimentally measured histological and cell kinetic parameters into a multiscale tissue modeling framework, we obtain results of population kinetics and proliferation index comparable to unirradiated and acutely irradiated swine experiments [3]. It is noted the basal cell doubling time is 10 to 16 days in the intact population, but drops to 13.6 hr in the regenerating populations surviving irradiation. This complex 30-fold variation is proposed to be attributed to the shortening of the G1 phase duration. We investigate this radiation induced effect by considering at the sub-cellular level the expression and signaling of TGF-beta, as it is recognized as a key regulatory factor of tissue formation and wound healing [4]. This integrated model will allow us to test the validity of various basic biological rules at the cellular level and sub-cellular mechanisms by qualitatively comparing simulation results with published research, and should lead to a fuller understanding of the pathophysiological effects of ionizing radiation on the skin.

FROM↗
NASA NTRS2018

Effects of Mitochondrial-Targeted Human Catalase in Skeletal Tissue of Mice Exposed to Simulated Spaceflight

During prolonged spaceflight, astronauts are exposed to both microgravity and space radiation and are at risk forincreased skeletal fragility due to bone loss, Evidence from rodent experiments has established that bothmicrogravity and ionizing radiation can cause bone loss due to increasd of bone-resorbing osteoclasts and decreasedin bone-forming osteoblasts, although the underlying molecular mechanisms for these changes are not fullyunderstood. We hypothesized that excess reactive oxidative species (ROS) produced by conditions that simulatedspaceflight alters the tight balance between osteoclast and osteoblast activities, leading to accelerated skeletalremodeling and culminating in loss of mineralized tissue. To begin to explore this hypothesis, we used the mCATmouse model [1]; these transgenic mice over-express the human catalase gene targeted to mitochondria, which arethe major organelle responsible for cellular production of free radicals. Catalase is an anti-oxidant that catalyzes theconversion of the reactive species, hydrogen peroxide (H202), into water and oxygen. This animal model wasselected as it displays extended lifespan, reduced cardiovascular disease and reduced central nervous systemradiosensitivity, consistent with elevated anti-oxidant activity conferred by the transgene. We reasoned that miceoverexpressing catalase the mitochondria of osteoblast and osteoclast lineage cells would be protected from the boneloss caused by simulated spaceflight.

CATALASE IN SKELETAL TISSUE↗
DOE OSTI2024

Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling

The hemorrhagic fever viruses (HFVs) cause severe or fatal infections in humans. Named after their common symptom hemorrhage, these viruses induce significant vascular dysfunction by affecting endothelial cells, altering immunity, and disrupting the clotting system. Despite advances in treatments, such as cytokine blocking therapies, disease modifying treatment for this class of pathogen remains elusive. Improved understanding of the pathogenesis of these infections could provide new avenues to treatment. While animal models and traditional 2D cell cultures have contributed insight into the mechanisms by which these pathogens affect the vasculature, these models fall short in replicating in vivo human vascular dynamics. The emergence of microphysiological systems (MPSs) offers promising avenues for modeling these complex interactions. These MPS or ‘organ-on-chip’ models present opportunities to better mimic human vascular responses and thus aid in treatment development. In this review, we explore the impact of HFV on the vasculature by causing endothelial dysfunction, blood clotting irregularities, and immune dysregulation. We highlight how existing MPS have elucidated features of HFV pathogenesis as well as discuss existing knowledge gaps and the challenges in modeling these interactions using MPS. Understanding the intricate mechanisms of vascular dysfunction caused by HFV is crucial in developing therapies not only for these infections, but also for other vasculotropic conditions like sepsis.

42 ENGINEERING↗
NASA NTRS1992

Altered immunological response in mice subjected to stress and exposed to fungal spores

Space flight and related factors such as stress appear to have an adverse effect on astronauts' immune systems. The presence of potentially pathogenic microbes including several genera of fungi reported from spacecraft environment may be a cause of concern in such situations. In order to study the role of such organisms in causing opportunistic or allergic diseases in crewmembers, we have tried to develop an animal model. BALB/c mice were suspended upside down for varying periods of time to induce stress, and their lymphocyte functions were evaluated. These studies indicate that the stress resulted in lowered mitogen induced lymphocyte stimulation as represented by 3H-thymidine uptake. We have also studied the ability of these animals to respond to Aspergillus fumigatus spores. The results of the study clearly demonstrate a definite down-regulation in T-cell proliferation and a higher incidence of infection with A. fumigatus.

Kurup, Viswanath P.↗
NASA NTRS2006

Structure and Function of the Snail Statocyst System after a 16-Day Flight on Foton-M-2

In terrestrial gastropod snail Helix lucorum L. we studied the changes after a 16-day exposure to microgravity in: behavior, neural responses to adequate motion stimulation, intersensory interactions between the photosensory pathways and the statocyst receptors, and in expression of the HPeP gene in the statocyst receptors. In behavioral experiments it was found that the latency of body position change to sudden orientation change (flip from horizontal to downwards position) was significantly reduced in the postflight snails. Extracellularly recorded neural responses of the statocyst nerve to adequate motion stimulation in the postflight snails were independent of the motion direction while in the control animals an orientation selectivity was observed. Significant differences in the HPeP gene mRNA expression pattern in the statocyst receptor neurons were observed in postflight (30h) and control snails. Obtained results confirm the possibility to elucidate the influence of microgravity exposure on mechanisms and function of gravireceptors using this simple model animal.

Balaban, P. M.↗
NASA NTRS1988

Correlation of macro and micro cardiovascular function during weightlessness and simulated weightlessness

The investigation of cardiovascular function necessarily involves a consideration of the exchange of substances at the capillary. If cardiovascular function is compromised or in any way altered during exposure to zero gravity in space, then it stands to reason that microvascular function is also modified. We have shown that an increase in cardiac output similar to that reported during simulated weightlessness is associated with a doubling of the number of post-capillary venules and a reduction in the number of arterioles by 35%. If the weightlessness of space travel produces similar changes in cardiopulmonary volume and cardiac output, a reasonable expectation is that astronauts will undergo venous neovascularization. We have developed an animal model in which to correlate microvascular and systemic cardiovascular function. The microcirculatory preparation consists of a lightweight, thermo-neutral chamber implanted around intact skeletal muscle on the back of a rat. Using this technique, the performed microvasculature of the cutaneous maximus muscle may be observed in the conscious, unanesthetized animal. Microcirculatory variables which may be obtained include venular and arteriolar numbers, lengths and diameters, single vessel flow velocities, vasomotion, capillary hematocrit anastomoses and orders of branching. Systemic hemodynamic monitoring of cardiac output by electromagnetic flowmetry, and arterial and venous pressures allows correlation of macro- and microcirculatory changes at the same time, in the same animal. Observed and calculated hemodynamic variables also include pulse pressure, heart rate, stroke volume, total peripheral resistance, aortic compliance, minute work, peak aortic flow velocity and systolic time interval. In this manner, an integrated assessment of total cardiovascular function may be obtained in the same animal without the complicating influence of anesthetics.

NASA Discipline Number 00-00↗