Fact Sheet
Text Size
Commercial Biomedical Test Module - 2 (CBTM-2)
03.23.09
Overview | Description | Applications | Operations | Results | Publications | Images
Experiment/Payload OverviewBrief Summary
Commercial Biomedical Test Module - 2 (CBTM-2) will use a validated mouse model to examine the effectiveness of an experimental therapeutic as a possible countermeasure for muscle atrophy. Combined with exercise, this experimental therapeutic developed by Amgen could one day form the basis for a treatment that will help maintain a high level of physical fitness in future flight crews. Also, through an extensive tissue sharing program several additional investigations will be performed on the effects of microgravity on the skeletal, cardiovascular, immune systems, liver and kidney function as well as other physiological systems.
Principal Investigator
BioServe Space Technologies, University of Colorado, Boulder, CO
Ames Research Center, Moffett Field, CA
Amgen Research, Thousand Oaks, CA
National Aeronautics and Space Administration (NASA)
Expeditions Assigned|15|
Previous ISS MissionsA similar investigation, CBTM, flew round trip to the ISS on STS-108 during ISS Expedition 4. AEMs have flown on numerous Space Shuttle missions over the years.
Experiment/Payload Description
Research Summary
- CBTM-2 research has the potential to contribute to the development of an effective countermeasure for the negative effects of space on human skeletal muscle. The muscle changes that occur as a result of space flight must be understood and addressed in order to send humans on long-duration missions to the Moon and Mars. Exercise is only partially effective in preventing muscle atrophy (wasting) during space flight. A complementary therapeutic countermeasure to muscle atrophy could make future missions to the Moon and Mars safer and more productive for space explorers.
- Mice will be flown in space where half will be treated with the muscle therapeutic and half given a placebo. Effects of treatment on muscle size and function will be compared between space flight and ground control mice.
- CBTM-2 could impact future long-duration missions by establishing a therapeutic approach to preventing or reducing the amount of muscle loss that occurs during long-duration space flight.
- CBTM-2 is also expected to contribute data to the current body of research on microgravity effects on organ systems through a tissue sharing program.
There are no approved pharmaceutical countermeasures to muscle loss for use in crewmembers or any currently in the NASA countermeasure "pipeline." To counter muscle atrophy currently, crewmembers engage in daily exercise while in space. Exercise routines last 1.5 - 3 hours per day and result in reduced crewmember productivity. These regimes also do not completely alleviate the muscle loss that occurs as a result of extended stays in space. Developing and approving a pharmaceutical countermeasure to this condition could be instrumental to long duration human exploration missions.
This investigation will examine the effectiveness of an experimental therapeutic in preventing muscle loss in mice exposed to microgravity. This will be the first time an experimental therapeutic for muscle loss will be investigated in space; an important and significant step in developing a more effective countermeasure to space induced muscle changes.
Physical deficits from muscle atrophy also affect millions of Americans and results in significant health care expenditures. This experimental therapeutic has the potential to benefit NASA crewmembers and could help inform the development of potential interventions for muscle wasting related to a range of diseases, including cancer, kidney failure and age-related frailty.
This research will utilize the animal enclosure modules (AEMs). Three AEMs will be flown; each containing eight mice for a total of twelve treated and twelve placebo control mice. Three AEMs in the same configuration as space will be operated on the ground as ground controls and run in parallel with the space flight modules.
This research is also expected to contribute data to the current body of research on microgravity effects on the skeletal, cardiovascular, and immune systems, liver and kidney function as well as other physiological systems through a tissue sharing program. Every effort will be made to harvest as many different samples and types of tissue from the mice as possible for other mission specific biomedical research. Positive results from this research may advance our understanding of mechanistic changes that occur in various physiological systems after exposure to microgravity and support overall efforts to reduce health risks to crewmembers. The investigations resulting from the CBTM-2 tissue sharing program are as follows:
- The effects of space flight on regulation of adipose (fat) tissues
- Relationship of microRNA expression and muscle atrophy in microgravity
- Space flight effects on mouse reproductive tissues
- Expression and localization of vascular myocyte calcium release channels
- Hypercalciuria during space flight: the role of calbindin D28K
- Muscle atrophy in microgravity: a case of imbalance between stem/progenitor cell activation and muscle cell death?
- Effect of space flight on macrophase differentiation and activation
- The effects of space flight on stress and immunity
- Space radiation and microgravity effects on regulation of lung tissue
- Effects of space flight on neurogenesis in the brain
- Effect of space flight on alterations of astrocyte-neuronal coupling
- Tissue-specific expression of gravity-sensitive proteins in kidney and liver
- Examination of functional and molecular changes caused by spaceflight-induced bone loss in mice
David Allen, Ph.D.
The goal of this research is to determine whether expression of certain components of a recently discovered regulatory pathway for muscle atrophy are changed in the fat tissue of mice during space flight. After space flight, two types of mouse fat tissue will be taken from the ground control and space flight animals. A chemical found in the body of all mammals, called ribonucleic acid or RNA will be separated from the mouse fat tissue samples and quantified. RNA is responsible for the transfer of information from deoxyribonucleic acid (DNA), genetic material, and plays an important role in protein synthesis (formation) and other chemical activity that occurs within the cells of the body. This research could lead to a better understanding of how crewmembers bodies are negatively affected by the microgravity environment and lead to new or improved treatments to counter those affects.
Brooke Harrison, Ph.D.
To date, few studies have investigated the effects of altered muscle use on muscle-specific micro-ribonucleic acid, microRNA (single strand RNA molecules) expression. The overall goal of this investigation is to identify microRNAs that demonstrate altered expression as a result of changes in muscle activation, specifically, muscle changes that occur during exposure to microgravity. To quantify microgravity-induced alterations in skeletal muscle microRNA expression, total RNA will be isolated from both ground control and space flight animals. The expression of selected microRNAs of interest will then be determined using Northern blotting (technique to study gene expression) or quantitative RT-PCR (reverse transcription - polymerase chain reaction, technique for amplifying a defined piece of a RNA) methods. Microgravity-induced alterations will be compared to ground-based models of both muscle use/disuse. This research could lead to a more thorough understanding of the mechanism behind the muscle atrophy that occurs during space flight, which could lead to the development of a countermeasure for this condition.
Allan Forsman, Ph.D.
The ovarian tissue of female mice is a rapidly changing tissue. Changes occur due to the rapid turnover of ovaries from the follicular phase (phase which ovary follicles mature) to the luteal phase (latter phase of the estrous cycle) of the four day estrous cycle in the mouse. Although follicular growth occurs over several estrous cycles the formation of the corpus luteum from the remnants of the follicle occurs within a relatively short time span, literally hours. Previous data has indicated decreased vascular endothelial growth factor (VEGF, signaling protein involved in formation of the embryonic circulatory system, and growth of blood vessels from pre-existing vasculature) levels in the ovaries of mice from ground-based models of space flight. These decreased levels of VEGF are believed to be due to decreased expression of the VEGF mRNA within the ovarian cells. This study will examine the gross morphology of the ovaries of the mice flown in space and the corresponding ground controls. Factors to be examined include ovarian/follicular/luteal size, shape, and overall tissue health. In the mouse, if the growth of the blood vessels that form within the corpus luteum is disturbed, the female mouse is unable to maintain a pregnancy. Understanding the effects of space flight on vessel growth in animal reproductive tissue may help scientists understand how the microgravity environment could affect the human reproductive system in space.
Jean-Luc Morel
This investigation examines the expression of calcium ion signalling proteins in vascular smooth muscles. The calcium ion signals are implicated in vascular tone and contraction but also in cellular processes including growth and differentiation. This investigation is based, in part, on results from a ground-based model of space flight. With this model, vascular smooth muscle change of calcium ion signalling was due to a decrease of ryanodine receptor (RyR, calcium channels in muscle) expression. This family of sarcoplasmic calcium ion channels (RyR) is crucial because these calcium ion channels amplify all calcium ion signals in smooth muscle cells.
The investigation will concentrate on calcium channels (RyR and the L and T-type voltage-dependent calcium ion channels, TRP channels, InsP3R) and on enzymes implicated in InsP3 and cyclic ADP-ribose (second messengers activating InsP3R and RyR, respectively) and vasoconstrictor receptor (adrenaline, angiotensin II, endothelin-1) regulating the activity of calcium ion channels. The investigation will compare animals in-flight, ground control and baseline groups and will help further the understanding of the effects of space flight on smooth muscles. Smooth muscle is responsible for the contraction of hollow organs, such as blood vessels, the gastrointestinal tract, the bladder, and the uterus.
Giovambattista Capasso, M.D.
This experiment investigates calcium metabolism, particularly as it relates to calcium excretion and re-absorption via the kidneys under space flight conditions. The importance of the membrane-transporter protein calbindin for calcium re-absorption is being investigated. In particular the focus is on the up and down regulation of the relevant gene, CaB, which is known to lead to effects on both sodium and calcium regulation in humans. Space flight and ground control mouse kidney tissue will be analyzed for this experiment. Disruption to the balance of calcium excreted and re-absorbed in humans during space flight is a significant complication that can lead to kidney stones during a mission. An improved understanding of how calcium loses its balance within the body may help to reduce or eliminate this complication for long-duration space missions.
Paolo Di Nardo, M.D.
Long duration exposure to microgravity induces skeletal and heart muscle deconditioning that can cause health concerns for crewmembers upon return to Earth. Several strategies are used to counteract muscle deconditioning, but the problem is still not completely solved. This is likely due to the fact that basic mechanisms behind gravitational atrophy (wasting) remain to be completely understood. The aim of this investigation is to evaluate whether there exists a possible imbalance between stem/progenitor cell recruitment and muscle cells in microgravity deconditioning and determine which biologically active factors are involved in the process. The results could be helpful in designing new strategies to avoid microgravity muscle deconditioning. This investigation will examine heart, diaphragm and skeletal muscle of the space flight and ground control mice.
S. Keith Chapes, Ph.D.
Space flight suppresses the formation of both red and white blood cells. It also affects the numbers of cells that circulate in the blood that protect people from disease. This occurs not only in humans but also in rats, mice and rhesus monkeys. In fact, space flight offers a unique environment that impacts many physiological systems. Amongst these systems, bone metabolism is known to be significantly altered by the skeletal unloading of space flight. Hematopoiesis is the process which forms red and white blood cells. Therefore, it provides the body with mature, functioning cells necessary for oxygenation, clotting and immune functions. The bone, specifically, the bone marrow, is the site for hematopoiesis. Moreover, changes in bone impact all compartments, including the bone marrow. Valuable information will be obtained about what changes occur in bone marrow cells from the STS-118 space flight and ground control mice. This understanding will allow for more effective countermeasure planning. On Earth, skeletal unloading occurs to individuals that are bedridden for long periods of time, wheel-chair bound, or lose the ability to stand for long periods of time. These prolonged periods of skeletal unloading also induce changes in bone that parallel those seen in space flight. In addition, individuals with bone disorders, such as osteoporosis, are also subject to alterations in hematopoiesis. Therefore, this experiment also has direct relevance to individuals on Earth.
Michael Pecaut, Ph.D.
There is an indisputable link between stress and immunity that is particularly important when discussing space flight. Although crewmembers will be exposed to isotropic whole-body radiation fields, simultaneous exposure to other environmental factors, such as microgravity and other mission-related stressors, could act additively, or even synergistically. Previous microgravity experiments have shown that exposure to the space flight environment can lead to changes in virtually all of the immune parameters influenced by radiation. This study is particularly interested in three inflammatory cytokines. All three cytokines are released by activated macrophages in response to a pathogenic challenge. In small localized amounts, these cytokines contribute to the immune response by regulating activity, enhancing phagocytosis, promoting coagulation, and stimulating growth and repair in damaged tissues. Additionally, all three have been linked to "sickness behavior" and, therefore, CNS-immune communication. This study will characterize both the stress response, and its effect on functional immune parameters ex vivo (outside) utilizing spleen, liver, brain, adrenal and thymus tissues. Results from the study may increase the understanding of the link between stress and immune system functioning in crewmembers during space flight and help develop strategies to minimize any negative effects.
Daila Gridley, Ph.D.
Previous studies on NASA Spacelab missions have found that pulmonary function in astronauts is greatly altered by weightlessness including diffusing capacity and reduced residual volume. Furthermore, inhalation of bacteria and fungi with increased antibiotic resistance and more rapid proliferation may adversely affect pulmonary function as well. We have recently compared effects of acutely delivered photons (gamma-rays), protons and simulated solar particle event protons (sSPE) on expression of extracellular matrix (ECM) regulators in lung tissue of mice. Transforming growth factor-beta1 (TGF-beta), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were assessed on days 4 and 21 after whole-body exposure to a total of 2-Gray (Gy). The data show dependence on radiation regimen in expression of these ECM regulators and suggest that lung function in crewmembers exposed to a large SPE may become compromised. This study proposes to examine the lungs' altered TGF-b1, MMP-2, TIMP-1 and TIMP-2 gene expression and for RT-Profiler PCR array, mouse oxidative stress and antioxidant defense. This research could lead to an increased understanding of overall pulmonary functioning during space flight.
Gregory A. Nelson, Ph.D.
Neurogenesis or the regeneration of new nerve cells is critical in maintaining cognitive function, learning and spatial memory in adult mammals. Neuronal stem cells are the most sensitive radiation targets in the central nervous system (CNS) and up to 50% loss of newly-born cells in the hippocampus (a critical structure for memory and learning) occurs at doses as low as 1-Gy. In mice and rats experimentally-induced reduction of neurogenesis has been shown to adversely affect learning and memory. The 1Gy level of exposure is anticipated for certain space operations such as extravehicular activities during a solar particle event (SPE). Therefore the potential for inhibition of neurogenesis by radiation with accompanying cognitive deficits is a significant risk factor for crewmembers. Neurogenesis is also highly dependent on stress levels (negative response) and environmental enrichment and activity (positive effect). Therefore space flight factors in general have the potential to influence neurogenesis and, by extension, memory and learning. This investigation will examine brain tissue for markers of neurogenesis and stress responses by a combination of immunohistochemistry on fixed tissue and Western blot analysis (method to detect protein) of key Wnt (regulate cell-to-cell interactions during embryogenesis) and IGF-1 (polypeptide protein hormone similar in molecular structure to insulin) pathway components from snap frozen samples.
Lora Green, Ph.D.
Recent preliminary data suggests that astrocytes (a type of brain cell) and neurons have reciprocal functional responses to irradiation and very different recovery kinetics. This investigation will examine the mechanism for this uncoupling by measuring alterations in glutamate uptake and metabolism, and to determine how abnormal glutamate uptake affects intercellular signaling with increased radiation exposure during space flight. The investigation will also examine brain tissue for markers indicative of astrocyte-neuronal coupling by immunohistochemistry and western blot analysis. Additionally, this study will assess the effect of space flight stress on intercellular communication in brain tissues. Immunofluorescence will be used to measure the expressed levels of the connexins known to be important in neuronal and astrocytic communication. Additionally, the study will examine the inter-relationship between calcium and adenosine triphosphate (ATP) during glio-transmission (neural transmission within astrocytes), by measuring the levels of the purinergic receptors in brain tissues from ground control and flight mice. Changes in astrocyte-neuronal coupling due to the radiation and/or microgravity components of the space flight environment may ultimately, result in cognitive deficits in crewmembers, thus an important area of investigation to ensure health and safety during space flight missions.
Timothy Hammond, M.D.
This investigation will test the hypothesis that there are tissue specific changes in renal and liver protein expression in space flight. If ICAM and VCAM protein expression are elevated in the liver but not the kidney then it can be confirmed that there are tissue specificity of the responses to space flight at the protein level. If there are changes in both tissues or neither tissue then the other forces present in suspension culture, but not space flight, are important mediators of ICAM and VCAM protein expression. If angiotensin converting enzyme (ACE, peptides (substances smaller than proteins) that act as vasoconstricting agents (causing blood vessels to narrow). Narrowing the diameter of the blood vessels sends up the blood pressure.) activity increases in-flight, either there is more ACE protein or the activity of the ACE is increased. This is important as ACE is the major degradatory enzyme for the vasoactive peptide angiotensin II (acts as an endocrine, autocrine, paracrine, and intracrine hormone). This investigation will utilize kidney and liver tissue provided by the tissue sharing program of CBTM-2. The choice of proteins to study is based on the gene expression data from a previous space flight investigation. This investigation will help determine if the gene expression changes observed translate into protein changes as well.
Ted Bateman, Ph.D.
This research will help develop a better understanding of weightlessness and its impact on the skeletal system. Currently crewmembers lose 1.5 - 2% of their skeletal mass each month during ISS missions, with bone strength declining ~2.5% per month. Due to improved analysis techniques over the last few years, a more in-depth analysis can occur. These improved techniques include microcomputed tomography (microCT), histology and immuno-histochemistry (IHC) all of which will be performed on the tibia of space flight and ground control samples. The humerus diaphysis (shaft of humerus) may also be used to examine levels of messenger RNA (mRNA) expression of specific genes including RANKL (Receptor Activator for Nuclear Factor Kappa B Ligand - a molecule important in bone metabolism; overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and osteomyelitis), OPG (osteoprotegerin, a cytokine that specifically acts on bone, increasing bone mineral density and bone volume) and osteocalcin (noncollagenous protein found in bone and dentin. It is secreted by osteoblasts and thought to play a role in mineralization and calcium ion homeostasis). This skeletal work will be performed in collaboration with BioServe Space Technologies and will include mechanical testing, compositional analysis and quantitative histomorphometry (identification of cellular and tissue components for the measurement of lengths) at the femur middiaphysis, middle shaft region of the femur.
The results of this research could be applied towards minimizing the risk of fracture in crewmembers during future exploratory missions to the moon and Mars. It will also help scientists better understand the molecular causes of bone loss in space and could have far reaching impact in furthering research in overall bone health.
Applications
Space Applications
Testing the effects of a potential countermeasure to the muscle loss that occurs during long-duration space flight will potentially provide NASA with a non-exercise, therapeutic countermeasure that helps ensure astronaut health and well being.
Earth ApplicationsMuscle atrophy resulting from disuse and reduced physical activity affects millions of Americans particularly in the aging population. This condition contributes to increased bone fractures, negative metabolic changes and decreased levels of physical activity. Results from this investigation could help inform the development of potential interventions for muscle wasting related to a range of disease, including cancer, kidney failure and age-related frailty.
Operations
Operational Requirements
Once the mice are in space, the flight hardware and experiment are relatively self-sufficient. The AEMs contain enough food and water to house the mice safely and effectively for the mission duration. An astronaut will check the health status of the mice on a daily basis, by assessing them through the viewing window on each AEM.
Operational ProtocolsFor this study nine week old female C57/B6 mice will be launched on the space shuttle. The mice will spend a total of 11-12 days in microgravity. Flight mice will be treated once with a placebo vehicle or therapeutic agent approximately 24 hours before launch. Ground control mice will be treated in the same manner but with a 48 hour offset. Ground control mice will be housed under the same environmental conditions (temperature, light/dark cycle, humidity, oxygen levels and carbon dioxide levels) as the flight mice. All mice will receive the same full access to food and water. Upon return to Earth, the AEMs will be returned to the research team for analysis. Body weight will also be measured pre and post flight. Statistical comparisons will be made between the treated and control mice.
Results/More Information
Information Pending
Related Web Sites
Publications
Results Publications
Related Publications
- Bar-Shai M, Carmeli E, Coleman R, Reznick AZ. Mechanisms in muscle atrophy in immobilization and aging. Annals of the New York Academy of Sciences. ;1019:475-478. 2004
- Harrison BC, Allen DL, Stodieck LS, Kostenuik PJ, Bateman TA, Morony, S, Leinwand, LA. Skeletal muscle adaptations to microgravity in the mouse. Journal of Applied Physiology. ;95:2462-2470. 2003
- Cannon CM, Dieter-Seelig H, Stodieck LS, Hanson AM, Simske SJ, Ferguson VL. A novel combination of methods to assess sarcopenia and muscle performance in mice. Biomedical Sciences Instrumentation. ;41:116-121. 2005
Images
NASA Image S118E09308: The Commercial Biomedical Test Module - 2 (CBTM-2) hardware seen in this image flew onboard STS-118/13A.1 in August 2007. CBTM-2 will test the effectiveness of an experimental therapeutic as a possible countermeasure for muscle atrophy.+ View Larger Image
Information Provided and Updated by the ISS Program Scientist's Office