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At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS2001

Cellular and molecular mechanisms for the bone response to mechanical loading

To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

Review↗
NASA NTRS1999

Molecular Mechanisms Regulating Muscle Fiber Composition Under Microgravity

The overall goal of this project is to reveal the molecular mechanisms underlying the selective and debilitating atrophy of specific skeletal muscle fiber types that accompanies sustained conditions of microgravity. Since little is currently known about the regulation of fiber-specific gene expression programs in mammalian muscle, elucidation of the basic mechanisms of fiber diversification is a necessary prerequisite to the generation of therapeutic strategies for attenuation of muscle atrophy on earth or in space. Vertebrate skeletal muscle development involves the fusion of undifferentiated mononucleated myoblasts to form multinucleated myofibers, with a concomitant activation of muscle-specific genes encoding proteins that form the force-generating contractile apparatus. The regulatory circuitry controlling skeletal muscle gene expression has been well studied in a number of vertebrate animal systems. The goal of this project has been to achieve a similar level of understanding of the mechanisms underlying the further specification of muscles into different fiber types, and the role played by innervation and physical activity in the maintenance and adaptation of different fiber phenotypes into adulthood. Our recent research on the genetic basis of fiber specificity has focused on the emergence of mature fiber types and have implicated a group of transcriptional regulatory proteins, known as E proteins, in the control of fiber specificity. The restriction of E proteins to selected muscle fiber types is an attractive hypothetical mechanism for the generation of muscle fiber-specific patterns of gene expression. To date our results support a model wherein different E proteins are selectively expressed in muscle cells to determine fiber-restricted gene expression. These studies are a first step to define the molecular mechanisms responsible for the shifts in fiber type under conditions of microgravity, and to determine the potential importance of E proteins as upstream targets for the effects of weightlessness. In the past year we have determined that the expression of E Proteins is restricted to specific fiber types by post-transcriptional mechanisms. By far, the most prevalent mechanism of cellular control for achieving post-transcriptional regulation of gene expression is selective proteolysis -through the ubiquitin -proteasome pathway. Steady-state levels of HEB message are similar in all fast and slow skeletal muscle fiber types, yet the protein is restricted to Type IIX fibers. HEB appears to be a nodal point for regulating fiber-specific transcription, as expression of the transcription factor is regulated at the post-transcriptional level. It is not clear at present whether the regulation is at the level of protein synthesis or degradation. We are now poised to evaluate the biological role of ubiquitination in fiber specific-gene expression by controlling the post-transcriptional expression of E Proteins. The use of metabolic labelling and pharmacological inhibitors of the ubiquitin pathway will be used to identify the mode of regulation of the Type IIX expression pattern. The potential role of specific kinases in effecting the restriction of HEB expression will be examined by using both inhibitors and activators. The results of these studies will provide the necessary information to evaluate the biological role of E proteins in controlling fiber type transitions, and in potentially attenuating the atrophic effects of microgravity conditions. We have also recently shown that ectopic expression of the HEB protein transactivates the Type IIX-specific skeletal a-actin reporter. The 218 bp skeletal a-actin promoter drives transgene expression solely in mature Type IIX fibers. A mouse also carrying the transgene MLCI/HEB (which ectopically expresses the E Protein HEB in Type IIB fibers) forces expression of the skeletal a-actin reporter gene in Type IIB fibers. We can now dissect the composition of this fiber-specific cis-element. The skeletal a-actin promoter is quite compact and has been extensively characterized in vitro for activity and binding factors. The single E box may act as a binding target of myogenic factor/HEB heterodimer to allow for IIX expression. The HEB transcription factor may recognize either the precise flanking sequences of the E Box, or perhaps interacting with other proteins bound nearby, and activating expression in Type IIX fibers. This E box will be both ablated, and alternatively, as ablation may well destroy any muscle-specific transcriptional activity, flanking sequences substituted with those surrounding the E box (El) of the myogenin promoter. Modification of fiber-specific transgene expression will be tested in transgenic mice. The results of these studies will provide basic information on the regulatory circuitry underlying fiber specificity, and will form the basis for building appropriate transgenic regulatory cassettes to effect fiber transitions in subsequent experimental manipulations on unweighted muscles.

Rosenthal, Nadia A.↗
NASA NTRS1997

Formation of Carbon Nanotube Based Gears: Quantum Chemistry and Molecular Mechanics Study of the Electrophilic Addition of o-Benzyne to Fullerenes, Graphene, and Nanotubes

Considerable progress has been made in recent years in chemical functionalization of fullerene molecules. In some cases, the predominant reaction products are different from those obtained (using the same reactants) from polycyclic aromatic hydrocarbons (PAHs). One such example is the cycloaddition of o-benzyne to C60. It is well established that benzyne adds across one of the rings in naphthalene, anthracene and other PAHs forming the [2+4] cycloaddition product (benzobicyclo[2.2.2.]-octatriene with naphthalene and triptycene with anthracene). However, Hoke et al demonstrated that the only reaction path for o-benzyne with C60 leads to the [2+2] cycloaddition product in which benzyne adds across one of the interpentagonal bonds (forming a cyclobutene ring in the process). Either reaction product results in a loss of aromaticity and distortion of the PAH or fullerene substrate, and in a loss of strain in the benzyne. It is not clear, however, why different products are preferred in these cases. In the current paper, we consider the stability of benzyne-nanotube adducts and the ability of Brenner's potential energy model to describe the structure and stability of these adducts. The Brenner potential has been widely used for describing diamondoid and graphitic carbon. Recently it has also been used for molecular mechanics and molecular dynamics simulations of fullerenes and nanotubes. However, it has not been tested for the case of functionalized fullerenes (especially with highly strained geometries). We use the Brenner potential for our companion nanogear simulations and believe that it should be calibrated to insure that those simulations are physically reasonable. In the present work, Density Functional theory (DFT) calculations are used to determine the preferred geometric structures and energetics for this calibration. The DFT method is a kind of ab initio quantum chemistry method for determining the electronic structure of molecules. For a given basis set expansion, it is comparable in accuracy to the MP2 method (better than Hartree Fock, but less accurate than more extensive electron correlation methods such as MP4 or CCSD). However, for systems with large numbers of basis functions it more efficient than any other methods that include electron correlation effects. In this presentation we show the results of DFT calculations for the reaction of benzyne with naphthalene, C60, and nanotube models. We compare energies for [2+2] and [2+4] cycloaddition products. The preferred products for the naphthalene and C60 reactions have been determined by experiment and, thus, these cases serve as a validation of our quantum chemical approach. We also compare the DFT and Brenner potential results. Finally we can predict the likelihood of reaction between benzyne and nanotubes.

Jaffe, Richard↗
NASA NTRS1999

Bone Blood Flow During Simulated Microgravity: Physiological and Molecular Mechanisms

Blood flow to bone has been shown to affect bone mass and presumably bone strength. Preliminary data indicate that blood flow to the rat femur decreases after 14 days of simulated microgravity, using hindlimb suspension (HLS). If adult rats subjected to HLS are given dobutamine, a synthetic catecholamine which can cause peripheral vasodilation and increased blood flow, the loss of cortical bone area usually observed is prevented. Further, mechanisms exist at the molecular level to link changes in bone blood flow to changes in bone cell activity, particularly for vasoactive agents like nitric oxide (NO). The decreases in fluid shear stress created by fluid flow associated with the shifts of plasma volume during microgravity may result in alterations in expression of vasoactive agents such as NO, producing important functional effects on bone cells. The primary aim of this project is to characterize changes in 1) bone blood flow, 2) indices of bone mass, geometry, and strength, and 3) changes in gene expression for modulators of nitric oxide activity (e.g., nitric oxide synthase) and other candidate genes involved in signal transduction of mechanical loading after 3, 7, 14, 21, and 28 days of HLS in the adult rat. Using a rat of at least 5 months of age avoids inadvertently studying effects of simulated microgravity on growing, rather than adult, bone. Utilizing the results of these studies, we will then define how altered blood flow contributes to changes in bone with simulated microgravity by administering a vasodilatory agent (which increases blood flow to tissues) during hindlimb suspension. In all studies, responses in the unloaded hindlimb bones (tibial shaft, femoral neck) will be compared with those in the weightbearing humeral shaft and the non-weightbearing calvarium (skull) from the same animal. Bone volumetric mineral density and geometry will be quantified by peripheral quantitative CT; structural and material properties of the long bones will be determined by 3-point bending (tibia, humerus) or compression (femoral neck) testing to failure. A unique aspect of these studies will be defining the time course of changes in gene expression in bone cell populations with unloading, accomplished with Northern blots, in situ hybridization, and immunohistochemistry. These studies have high relevance for concurrent protocols being proposed by investigators on NSBRI Cardiovascular and Muscle teams, with blood flow data available on a number of tissues other than bone. Further, dobutamine and other Beta-agonists have been tested as countermeasures for altered muscle and cardiovascular function. Results of the intervention tested in our studies have potential relevance for a number of systemic changes seen with prolonged spaceflight.

Bloomfield, Susan A.↗
NASA NTRS2011

Molecular Mechanisms of Circadian Regulation During Spaceflight

Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4 immunofluorescence. Opn4 was decreased (abrogated in one case) in retinas that concurrently showed higher evidence of oxidative stress. We propose that oxidative stress can lead to a decrease in melanopsin expression, likely via ipRGC loss or impairment, and thus, it can be a contributing factor to circadian disruption during spaceflight. Countermeasures contemplating the use of light should therefore be complemented with melanopsin expression maintenance and/or reduction in oxidative stress.

Zanello, Susana↗
NASA NTRS2012

Molecular Mechanisms of Circadian Regulation During Spaceflight

The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight.

Zanello, S. B.↗
NASA NTRS1989

Neoplastic cell transformation by high-LET radiation - Molecular mechanisms

Quantitative data were collected on dose-response curves of cultured mouse-embryo cells (C3H10T1/2) irradiated with heavy ions of various charges and energies. Results suggests that two breaks formed on DNA within 80 A may cause cell transformation and that two DNA breaks formed within 20 A may be lethal. From results of experiments with restriction enzymes which produce DNA damages at specific sites, it was found that DNA double strand breaks are important primary lesions for radiogenic cell transformation and that blunt-ended double-strand breaks can form lethal as well as transformational damages due to misrepair or incomplete repair in the cell. The RBE-LET relationship for high-LET radiation is similar to that for HGPRT locus mutation, chromosomal deletion, and cell transformation, indicating that common lesions may be involved in these radiation effects.

Yang, Tracy Chui-Hsu↗
NASA NTRS2000

Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease

The RNA and DNA tumor viruses have made fundamental contributions to two major areas of cancer research. Viruses were vital, first, to the discovery and analysis of cellular growth control pathways and the synthesis of current concepts of cancer biology and, second, to the recognition of the etiology of some human cancers. Transforming retroviruses carry oncogenes derived from cellular genes that are involved in mitogenic signalling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events. Viruses are now accepted as bona fide etiologic factors of human cancer; these include hepatitis B virus, Epstein-Barr virus, human papillomaviruses, human T-cell leukemia virus type I and hepatitis C virus, plus several candidate human cancer viruses. It is estimated that 15% of all human tumors worldwide are caused by viruses. The infectious nature of viruses distinguishes them from all other cancer-causing factors; tumor viruses establish long-term persistent infections in humans, with cancer an accidental side effect of viral replication strategies. Viruses are usually not complete carcinogens, and the known human cancer viruses display different roles in transformation. Many years may pass between initial infection and tumor appearance and most infected individuals do not develop cancer, although immunocompromised individuals are at elevated risk of viral-associated cancers. Variable factors that influence viral carcinogenesis are reviewed, including possible synergy between viruses and environmental cofactors. The difficulties in establishing an etiologic role for a virus in human cancer are discussed, as well as the different approaches that proved viral links to cancer. Future directions for tumor virus studies are considered.

NASA Program Biomedical Research and Countermeasur↗
NASA NTRS2014

Maiden Voyage of the Rodent Habitat on ISS: Opportunities for Investigating Molecular Mechanisms and Biomedical Consequences of Long Duration Spaceflight

Research using rodents is an essential tool for advancing biomedical research 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, flight hardware, operations, and science capabilities were developed at NASA ARC to support both commercial and government-sponsored research. In preparation for the maiden voyage of the Rodent Habitat hardware and operations system (Rodent Research-1), and in close consultation with a Science Working Group comprised of veterinarians and experienced spaceflight investigators, we modified existing Animal Enclosure Module hardware, developed new hardware, operations, and science activities, and performed a series of ground-based verification tests. Preflight, ground based hardware tests included a simulation of SpaceX Dragon launch conditions (vibration and hypergravity) using the Transporter, and also two long-term biocompatibility tests (32 and 92 days) using the Habitat developed for long term housing on the ISS. The launch simulation test showed that adult mice housed in Transporter hardware adapted well, even if launch simulation was followed by a period of simulated weightlessness (via hind limb unloading). The biocompatibility tests demonstrated that the Habitat successfully supported animal health and also provided a useful video imaging system that enables frequent monitoring of animal health and behavior by veterinary and scientific experts on the ground, independent of ISS crew intervention. At the conclusion of all tests, mice were deemed healthy and suitable for conducting biological research. Additional preflight analyses of tissues preserved by freezing or fixation for gene expression analyses revealed that spleen and liver tissues recovered under conditions that simulated on-orbit activities yielded high quality RNA (RIN values 8-10) and liver enzyme activities and protein content (e.g. catalase). In addition, new methods were developed to optimize future science return by dissecting tissues post-euthanasia and storage. Various tissues were harvested from either intact or partially dissected, frozen carcasses after storage for ~2-6 months; most of the tissues (brain, heart, kidney, eye, adrenal glands and skeletal muscle) were of high RNA quality for science return, whereas some tissues (small intestine, bone marrow and bones) were not. These data demonstrated the protocols developed for future flight experiments supported science return despite delayed preservation post-euthanasia or prolonged storage, and furthermore, that high-quality RNA samples from many different tissues can be recovered by dissection following prolonged storage of the tissue in situ at -80˚C. The first flight experiments carrying 20 mice were launched on Sept 21, 2014 in an unmanned Dragon Capsule, SpaceX4; Rodent Research-1 is dedicated to achieving both NASA validation and CASIS science objectives. Ground based 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. The 10 mice for 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 on Oct 12 and 13, 2014, and the validation mice will reside on ISS for up to 30 days. In conclusion, new capability for long duration rodent research is under development, including in-flight sample collection (which avoids the complication of reentry); results obtained to date will be described. This new Rodent Research system enables achievement of both basic science and translational research objectives to advance human exploration of space.

maiden voyage↗