To demonstrate its commitment to research in the physiological challenges of manned space flight, Vanderbilt University Medical Center established the Center for Space Physiology and Medicine in 1989. Under the direction of David Robertson, M.D., Professor of Medicine, Pharmacology, and Neurology, and F. Andrew Gaffney, Professor of Medicine, the Center's mission is to direct and coordinate the Medical Center's space-related research. The collaborating members of the medical faculty are internationally recognized authorities in many areas relevant to manned space flight. The Center also has close ties to scientists within NASA centers and to Russian investigators in the Institute for Biomedical Problems and the Russian Cardiological Research Center in Moscow.
For information about fellowships and research opportunities, please contact: David Robertson, M.D., Director, Center for Space Physiology and Medicine, AA-3228 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2195, U.S.A., E-mail: email@example.com .
Vanderbilt University is home to international authorities on many aspects of space physiology and medicine. Vanderbilt's General Clinical Research Center (GCRC) provides an ideal setting for their research.
Supported by the National Institutes of Health, the GCRC's objective is to improve the understanding of diseases and develop better methods of treatment. It ranks among the oldest and largest general research centers in the world. The Center's clinical facilities occupy more than 18,000 net square feet. Research and diagnostic laboratories and facilities, including a metabolic kitchen, support the patient unit.
The GCRC hosts about 200 active clinical research projects of some 160 basic and clinical investigators, many recognized worldwide as experts in their fields. The unit has 53 professional support staff, each carefully selected on the basis of specialized training, clinical ability, and experience.
Patients and normal volunteers on the GCRC may undergo specialized testing, which in some cases is available only at Vanderbilt. It is through these means that the physician/medical researcher collects scientific data necessary for elucidating the cause of human disease.
Space-related activities are not new to Vanderbilt. Dr. Raphael Smith conducted studies during the Skylab missions in the 1970's. In 1989, Vanderbilt established the Center for Space Physiology and Medicine to bring together investigators sharing an interest in space-related research, and allocated resources to encourage the development of this field at our institution. Vanderbilt participated in NASA's Neurolab mission in 1998 and the Mir missions of the Russian, American, and German space agencies in 1997 and 1998. There are close ties with NASA intramural scientists in Johnson Space Center and Ames Research Center.
In addition, Vanderbilt medical scientists are continuing an exchange program, begun in 1984, with investigators at the Russian Cardiovascular Research Center in Moscow. This collaboration is conducted through Dr. Vsevolod Tkachuk, who directs the Department of Molecular Endocrinology, and Dr. Oleg Yurievich Atkov, the Russian cosmonaut-physician who directs the Department of Novel Technology. Through this link, Vanderbilt researchers have the opportunity to share information with the Russian colleagues and co-investigators who have experience in space cardiovascular research.
Neurolab was a shuttle mission dedicated to research on the nervous system and behavior. Neurolab used the Spacelab module to conduct an integrated, coordinated program of life sciences research. The goals of Neurolab were to study basic research questions in the neurosciences and to increase understanding of the mechanisms responsible for neurological and behavioral changes in microgravity. This information contributed to our understanding of normal and pathological neurological conditions and can be applied to enhancing the treatment of human disease.
Neurolab was launched in April 1998 (STS-89) aboard Columbia with a crew of seven on a mission of 16 days. It represented a collaboration among scientists from many countries including Germany, France, Canada, and many institutions in North America. Support for the mission was provided primarily by the National Institutes of Health and NASA.
Vanderbilt's Neurolab project was designed to probe how the autonomic nervous system functions in microgravity. Careful studies of norepinephrine and its metabolism, microneurographic sympathetic nerve traffic, and norepinephrine spillover were combined to provide a comprehensive picture of autonomic physiology in microgravity. Vanderbilt participants in the Neurolab autonomic project included Drs. David Robertson, Italo Biaggioni, Rose Marie Robertson, Andrew C. Ertl, Andre' Diedrich, Lynda Lane and F. Andrew Gaffney. The Neurolab autonomic project included collaboration with C. Gunnar Blomqvist in Dallas, Texas, Friedhelm Baisch in Cologne, Germany, and Dwain Eckberg in Richmond, Virginia.
The response of intravascular volume, blood pressure and cardiovascular fitness to microgravity is of obvious importance to the design of both orbital and extra-orbital space travel facilities. Of equal or even greater importance is the response of these physiologic factors to the return to 1g (or greater) environments.
Reflex and neurohumoral aspects of cardiovascular control have recently become a major focus of the U.S. space program, in spite of technological limitations at the time of early flights (Skylab) and the short duration of the more recent shuttle flights. The Russian program has also addressed this problem to some extent on longer duration flights, but post-flight orthostatic intolerance remains a problem.
Dr. Tadashi Inagami, Professor of Biochemistry and Medicine and Director of Vanderbilt's Hypertension program, has made many contributions to the field of blood pressure control. He elucidated the structure of renin, ANF, and the angiotensin receptors, and has recently identified a physiological role for joining peptide (JP), a derivative of the proopiomelanocortin gene whose function was previously unknown. He is studying the possible role of this peptide in central control of the cardiovascular system. With Dr. Masaaki Tamura, he is also focusing on the regulatory mechanism of catecholamine production and release in adrenal medulla.
As a central shift of intravascular volume may occur in space, a clear understanding of the regulation of important vasoactive and natriuretic compounds and their effects in simulated and real microgravity conditions would be important to the understanding of volume and vascular tone control in space.
The investigations of Dr. Rose Marie Robertson have recently begun to characterize the role of circulating dopa in volume homeostasis. This compound, which is the precursor of dopamine, and thus central in the neuronal synthesis of norepinephrine, may have an additional role in controlling intravascular volume. It can be converted to dopamine extra-neuronally and may exert a natriuretic and diuretic effect after conversion. It has been suggested that the production of dopa can be affected by dietary manipulation and by sympathetic state. As this endogenous compound may play a role in volume regulation during space flight, the ability to modulate its production would be of great importance.
Drs. David Robertson, Rose Marie Robertson, Italo Biaggioni, F. Andrew Gaffney, and John R. Shannon have a long-standing interest in neural control of the circulation. Studies in normal volunteers have addressed the importance of sodium balance in neuroadrenal function and have defined normal sympathoadrenal responses to standard physiologic maneuvers such as tilt, cold pressor and automated baroreflex stimulation and pharmacologic interventions with agents such as tyramine, adenosine and caffeine.
The definition of these responses includes precise determination of circulating catecholamines, invasive and non-invasive hemodynamic measurements (heart rate, blood pressure, cardiac output, right and left atrial pressures) and direct (microneurographic) measurement of sympathetic nerve activity. Cardiac volumes are determined with 2-dimensional echocardiography. Evaluation of the role of relevant substances (adenosine, caffeine, glutamate) in the central nervous system utilizes stereotactic studies of specific brainstem nuclei in rats.
Dr. Raphael Smith, Chief of the Cardiology Section at the Nashville Veterans Affairs Hospital, was responsible for the analysis of electrocardiographic data during the Skylab missions. The incidence of arrhythmias during space flight has been a continuing matter of concern and remains poorly understood. Drs. David E. Hansen and Dan M. Roden have demonstrated in an isolated, supported canine heart that myocardial stretch alters the electrophysiologic properties of myocardial tissue in such a way as to promote ventricular extrasystoles. It may well be that specific stretch-operated channels are directly relevant to the incidence and potential control of ventricular arrhythmias associated with the central volume shifts seen with space flight.
In 1978 Vanderbilt University became the first institution to establish a clinic devoted exclusively to the diagnosis and treatment of disorders of autonomic blood pressure regulation. In the years since then, under the leadership of Drs. David Robertson and Italo Biaggioni, this Autonomic Dysfunction Center has gained broad experience in the pathophysiology of orthostatic hypotension and has become an international referral center for patients with various forms of chronic hypotension and orthostatic intolerance.
Investigators in Vanderbilt's Autonomic Dysfunction Center have identified previously unrecognized disorders producing orthostatic hypotension, including dopamine-beta-hydroxylase deficiency, a syndrome in which patients have a congenital absence of norepinephrine and epinephrine, and norepinephrine transporter deficiency, which gives rise to orthostatic intolerance. The investigators have introduced novel therapeutic modalities for the management of orthostatic hypotensive patients. They are also studying the consequences of baroreflex failure in human subjects. Patients with orthostatic intolerance represent a uniquely appropriate model for the hemodynamic abnormality seen in astronauts returning to earth following space flight . Many of the therapeutic approaches used in treating orthostatic hypotensive patients have yet to be studied as potential countermeasures for the orthostatic intolerance associated with space adaptation.
One of the closest models of the cardiovascular complications of the microgravity environment is orthostatic intolerance. In this disorder, blood pressure may fall slightly on assumption of upright posture, remain the same, or even increase. However, heart rate commonly rises more than 30 beats per minute on standing. Orthostatic intolerance is common and as many as 500,000 Americans may experience it sometime in their lives.
In recent investigations, the staff of the Autonomic Dysfunction Center, including Drs. Italo Biaggioni, Andrew Ertl, Giris Jacob, John Shannon and Jens Jordan, have identified several different pathophysiologic mechanisms underlying orthostatic intolerance. These include partial dysautonomia, central hyperadrenergia, and norepinephrine transporter deficiency. These recent findings should lead to better understanding of this disorder and similar disorders such as the chronic fatigue syndrome. Orthostatic intolerance goes under many different names (mitral valve prolapse syndrome, postural orthostatic tachycardia syndrome, idiopathic hypovolemia, and vasoregulatory asthenia) but all probably share a common pathophysiology.
Sanford B. Krantz, M.D., Professor of Medicine is an international authority on the causes and treatment of anemia. Dr. Krantz has been involved in the study of erythropoietin (the hormone which regulates red cell production) and erythropoiesis since the early 1960's.
One of the complications of prolonged weightlessness is the development of mild anemia associated with reduced red cell production and low reticulocyte response. Strict bedrest has been used as an earth-bound model of space flight, and a qualitatively similar decrease in red cell mass has been found. There is evidence to indicate that this anemia of space flight and bedrest is due to decreased production of red cells rather than hemolysis. Dr. Krantz and his collaborators hypothesize that the decrease in sympathetic nervous system activity produced by bedrest contributes to this decrease by causing impaired erythropoietin production. In agreement with this hypothesis, Dr. Biaggioni and Dr. Robertson have found anemia with impaired erythropoietin production in patients with pure autonomic failure and Shy-Drager Syndrome (multiple system atrophy). This group is conducting research to determine if sympathetic activity modulates the erythropoietin response in humans and if the loss of red cell mass can be prevented by sympathetic activation.
Dr. Krantz interacts with a team of five physicians currently involved in the research of erythropoietin. By conducting studies from various points of view--metabolic, physiological and biochemical--the team brings great depth to this research.
Recently, there has been increased interest in the reaction of muscles to disuse and weightlessness in space. Dr. Wolf-Dietrich Dettbarn, Professor of Pharmacology, is studying this phenomenon that may limit man's tolerance to space flight.
Dr. Dettbarn is using the hind limb suspended (HLS) rat to investigate temporal changes in morphological, biochemical, and physical characteristics of slow and fast muscles as they are produced by disuse. Fast muscles, as the name suggests, are muscles that contract quickly and are used by the body for ambulation. Likewise, slow muscles contract slowly and work as antigravity muscles.
In space, the slow muscle undergoes a change to take on the characteristics of the fast muscle. This change causes astronauts to experience difficulty with walking and circulation once back on earth.
Dr. Dettbarn is currently using the HLS rat as a model for understanding the nature of muscle atrophy in space and to find ways in which this process can be prevented or reversed.
Dr. Dettbarn's current studies concern the following :
The human counterpart of these experiments includes studies conducted by Drs. Jane H. Park of the Department of Radiology, Gerald Fenichel of the Department of Neurology, Italo Biaggioni, Fernando Costa, and Andrew C. Ertl. The effects of simulated weightlessness on muscle function and fatigue and on the activity of muscle sympathetic afferents may be determined quantitatively by the use of new, non-invasive methods available at Vanderbilt. Magnetic resonance spectroscopy measures phosphorus compounds (energy state) in muscle. The rectified integrated electromyogram provides a running average of total electrical activity, allowing the determination of the number of motor units recruited to maintain a force. In addition, magnetic resonance imaging is available for evaluating morphological changes in muscle and surrounding tissues. These non-invasive measures will be coupled with information obtained by direct measurement of muscle sympathetic nerve traffic with microneurography. Isometric and isotonic exercises are being used to stimulate muscle sympathetic afferents during acutely induced fluid shifts and with bed rest deconditioning.
Since a number of physiological determinants are known or are suspected to be affected by zero gravity it is quite likely that space flight will challenge a drug's pharmacokinetics. Dr. Grant R. Wilkinson, Professor of Pharmacology and Director of the Clinical Pharmacology Training Program, investigates this area.
Dr. Wilkinson's intent is to establish the significance of microgravity-induced changes in physiology. His two approaches include animal and human models using bed rest to simulate microgravity. To examine individual variability in drug responsiveness with simulated microgravity, two areas will be addressed: the absorption, metabolism, and distribution of drugs; and, pharmacodynamics - or how drugs work at the site of action.
Dr. Wilkinson's approach for the collection of physiological information follows.
One of the most striking findings from space missions and earth-based simulations of weightlessness is the rapid and continuous loss of bone mineral and alterations in skeletal mass. The major health hazards associated with skeletal bone loss are accumulations of excess mineral in tissues such as the kidney, increased risk of fracture, and potentially irreversible damage to the skeleton. Studies are being conducted at both the molecular and systemic level to address this problem.
Vanderbilt investigators are attempting to elucidate the molecular events regulating osteoblast differentiation. Previous studies have indicated a decrease in the number of differentiated osteoblasts and an increase in undifferentiated precursor cells during exposure to microgravity, suggesting an arrest in maturation . Current studies of the molecular regulation of the expression of creatine kinase-B, the predominant isoenzyme in bone and a pivotal enzyme in cellular energy transduction, and its behavior in response to mechanical stretch and microgravity should clarify the mechanisms mediating differentiation and subsequent maturation of osteoblasts.
Vanderbilt's Department of Mechanical Engineering, in conjunction with the Department of Orthopaedics and Rehabilitation and the Department of Radiology, is conducting research to understand the phenomenon of bone loss at the systemic level. Their studies focus on the development of practical measures necessary for long-term survival during lengthy space missions. Research conducted on human volunteers will be used to develop physical laws for predicting the temporal changes in skeletal structure in response to altered activity, and will provide much needed data with which to validate and refine a theoretical model for skeletal adaptation to altered activity and gravity. The latter will provide specific guidelines for the prevention of disuse osteoporosis during long-duration space flight, such as Moon and Mars missions.
There is a great deal of interest in how space travel alters body weight regulation. The Vanderbilt Clinical Nutrition Research Unit (CNRU), directed by Raymond F. Burk, M.D., is involved in research into the mechanisms of body weight regulation. This expertise can readily be applied to problems of body weight regulation in space.
Ming Sun, Ph.D. and Kong Chen, Ph.D. direct the Energy Balance Laboratory of the CNRU. The strength and uniqueness of the laboratory lie in the use of indirect calorimetry to measure energy expenditure and physical activities (metabolic rate) in many situations and following a variety of manipulations, such as exercise and dietary changes. The laboratory, for example, contains one of the few existing whole-room, live-in calorimeters for measuring metabolic rate continuously over long periods of time (24 hours or longer) and contains a unique force platform system for exercise and physical activity evaluation. Use of this instrument allows direct assessment of nutritional and physiological questions that previously could not be addressed directly with short-term measures of energy expenditure.
Current research is focused on finding determinants of energy expenditure and body weight regulation. Effects on energy metabolism of other types of interventions (e.g., nutrient intake, environmental temperature changes, etc.) can be assessed. Environmental parameters may be tightly controlled so that the effects of, for example, environmental temperature on metabolic rate can be studied. A major advantage of the whole-room calorimeter is the ability to determine daily balances of protein, fat and carbohydrate. Oxidation rates of each are determined using the whole-room calorimeter and intakes are determined by the GCRC nutritional staff. This procedure allows detection of small changes in stored protein, fat or glycogen that would not be obtainable by measures of body composition.
The live-in chamber is located in the Vanderbilt Clinical Research Center. This is an optimum location since it allows the investigator to maintain precise control over nutritional intake during experiments. We can for example, assess the effects of amount or type of food eaten on energy expenditure or body composition. Additionally, we can vary exercise, physical activity, and any nutrient in the diet to assess effects on energy metabolism and body composition. Several of the most accurate methods of measuring body composition are used, including hydrostatic weighing and bioelectrical impedance. This provides information on the composition of any observed changes in body weight.
Vanderbilt University's Center for Microgravity Research and Applications is headed by Dr. Taylor Wang, an astronaut-scientist in the space shuttle program. Dr. Wang was selected by NASA in June 1983 to train as a space shuttle astronaut-scientist for Spacelab-3, a research facility flown in the cargo bay of the space shuttle. He flew as one of a seven-member crew on this mission and studied the dynamic behavior of rotating spheroids.
Dr. Wang is the inventor of the acoustic levitation and manipulation chamber. He is the recipient of NASA's Exceptional Scientific Achievement Medal and the NASA Space Flight Medal.
Dr. Wang's team is conducting experiments both in space and in terrestrial laboratories to study physics, fluid mechanics, materials science and medical applications without the adverse effects of gravity and containers.
Another engineering faculty member, Dr. D. L. Kinser, investigates the important area of the reaction of ceramics in space.
Faculty members from the Department of Mechanical and Materials Engineering led by Dr. Alvin M. Strauss are working on a number of device designs for space application.
One study in particular is investigating the mobility of human beings in space suits. Researchers are seeking to develop accurate models of the interaction between the human musculoskeletal system and the space suit. Other research is aimed at acquiring vital data on the internal geometry of the musculoskeletal system. Volume-rendering algorithms are being developed to display and manipulate large three-dimensional volume data sets generated by computed tomography and magnetic resonance scanners or cadaveric sectioning. This data will create an anthropomorphic data base which the musculoskeletal modeling requires. The volume data will be collected into more conventional boundary representation solid models used in computer-aided design (CAD) systems. By representing the anatomic information in a standard CAD format, designers will be able to access anthropomorphic data directly during the design of space suit components.
In the later stages of the research project, muscle dynamics will be incorporated into the mobility analysis to evaluate operator fatigue. Many models of the human musculoskeletal system assume that the muscle travels in a straight line between points of muscle insertions. This kinematic model is extremely poor since the muscle's three dimensional structure forces it to bend around the bones and other muscle masses. Using continuum mechanics, methods will be sought to model the string-like character of muscle fibers. These models will improve the software's ability to determine operator fatigue in the design of space suits and other astronautical appliances.
The second study which is part of this research project is the experimental evaluation of space suit mobility. Records of astronaut performance can be made by attaching landmarks to the various components of the space suit and using video cameras to film astronauts performing various tasks in simulated reduced/zero gravity environments. Using at least two video cameras and the appropriate calibration apparatus, the three dimensional motions of the landmarks can be determined. These three dimensional landmark motions can be converted into rigid body descriptions of the space suit segments which can subsequently be compared to the theoretically predicted data.
Preserving the functional advantage of the hand in an exoskeletal suit without placing excessive energy demands for movement has proven to be one of the most complicated tasks confronting space suit designers. Vanderbilt researchers are addressing several design and control issues in the design of a power-assisted space glove.
New technology will be required to develop methods of sensing the environment and actuating the glove. Actuation schemes include the use of pressurized bladders inside the fingers of the glove. By controlling the fluid pressure inside these bladders, forces which assist the actual finger movements could be generated.
Another generator of new technology is the development of sensors to provide touch and force feedback to the control system of the hand. Research work under the direction of Dr. Strauss has already led to the development of a combined surface shear force/pressure sensor. A big advantage of this technology is that electronic circuits can be manufactured along with the sensing element, thereby reducing cost of production.
Vanderbilt was one of 21 universities in the U.S. to be chosen in 1989 for the NASA Space Grant College and Fellowship Program. Dr. Strauss serves as the Tennessee Valley Space Grant Consortium director, leading the efforts of Tennessee State University, Fisk University, University of Tennessee Space Institute, and Vanderbilt University in the areas of space science and engineering.
It has long been recognized that the neurovestibular system is especially challenged by the environment of weightlessness. The complex adaptive process it undergoes when astronauts reach microgravity is probably central to the syndrome of space motion sickness, which causes reduced work efficiency, interferes with nutrition, and contributes to a sense of disorientation.
One of the most prominent consequences of neurovestibular disturbance, nausea, is closely linked to parasympathetic activation and concomitant sympathetic withdrawal. Working on the assumption that improved methods for relieving space motion sickness would improve the altered autonomic function that presumably contributes to other physiological abnormalities in microgravity, Drs. Fernando Costa, Patrick Lavin, and Italo Biaggioni are collaborating in an effort to clarify this link.
Two approaches are being taken. First, they are using ground-based models of vestibular disturbance to induce nausea in volunteers as they screen them for reduced sympathetic activation. Second, they are studying new pharmacologic approaches to the prevention of space motion sickness and applying pharmacokinetic modeling to guide dosing of these drugs.
Current NASA supported work in this area is being conducted by Italo Biaggioni, Andre' Diedrich, and Fernando Costa in a collaboration between Vanderbilt University investigators and Drs. Horacio Kaufmann and Bernard Cohen at Mt. Sinai Medical School.
An essential component of many of the studies conducted by Center researchers is the mathematical modeling of physiological responses. Dr. Jerry C. Collins, Associate Professor of Biomedical Engineering, has many years of experience in the modeling of biological systems. In collaboration with other institutions and with biomedical engineering students from Vanderbilt, Dr. Collins is currently developing several important models for defining the physiological responses to the stresses of real and simulated microgravity to complement the work of Center researchers.
Dr. Collins's work addresses the assumption of Center researchers that fluid volume shifts and other physiological changes associated with microgravity result in a modification of sympathetic activity which alters still further cardiovascular response and control. A model of whole-body microvascular transport and cardiac and cardiovascular dynamics is proposed that would account for fluid shifts by analyzing such variables as vessel lumen diameter, wall tension, tensile force, and pressure. Another model currently being developed proposes to characterize heart rate changes as a function of carotid sinus, aortic arch, and cardiopulmonary baroreceptor activity. Still another recently developed compartmental model of the pharmacokinetics of L-dopa and its principal metabolites will be adapted to the study of circulating dopa in volume regulation. Resources available in the Clinical Research Center for simulation of microgravity (head-down tilt, lower-body negative pressure, neck cuff pressure and suction, and pharmacological interventions) are being used in the development of these models.
Results from these and other modeling analyses will not only provide insights into the physiological problems of man in space, but will also have direct application to such clinical problems as the regional accumulation of fluid during heart failure and its redistribution and resolution following the administration of diuretics and other vasoactive drugs.
Use of Diagnostic Sonography During Long Duration Space Flight
Dr. Arthur Fleischer's research involves conceptualization and testing the uses of diagnostic sonography in a variety of disorders that may occur during long duration space flight. It can be predicted that due to its versatility, low cost, and minimal operational needs, diagnostic sonography will be extensively utilized during long duration space flight. Some of the applications of this modality include the investigation of cardiac contractility and physiologic changes due to space, its use for diagnosis and acute trauma such as its use to diagnose an Achilles tendon tear, acute abdominal and pelvic disorders. Changes in bone density can also be monitored during bone sonometry. Other issues involved in "space" ultrasound is whether a short training period is sufficient for the space crew to perform and accurately diagnose in real-time, complexities of transmitting the obtained sonographic image to experts on the ground, and problems related to telesonography, the transmission and receipt of images from outer space.
Understanding How Ion Channels Sense Mechanical Force
The electrical activity of cells is controlled by plasma membrane ion channels. Ion channels are opened and closed or gated by chemical ligands, voltage differences across the membrane or mechanical force. Mechanosensitive channels play central roles in fundamental physiological processes such as the perception of sound, touch and gravity; coordination of muscle contractions; cell volume regulation; cell motility; and regulation of systemic fluid balance and blood pressure. Alterations in the activity of mechanosensitive ion channels may underlie certain pathophysiology associated with space travel such as cardiac arrhythmias, disorders of systemic fluid balance, bone loss, hypotension and neurovestibular disturbances.
Regulation of channels by ligands and membrane voltage has been studied extensively and, in some cases, is understood at a molecular level. In contrast, almost nothing is known about how channels sense mechanical forces. The presence of mechanically gated channels in virtually all cell types, and the lack of highly selective inhibitory ligands has greatly hindered attempts to understand the molecular basis of mechanosensitivity.
Dr. Kevin Strange is Professor of Anesthesiology and Pharmacology, and Director of the Anesthesiology Research Division. His laboratory has had a longstanding interest in elucidating the physiology and biophysics of membrane proteins that sense and respond to mechanical forces and changes in cell size. Recently, his laboratory developed methods to patch clamp C. elegans embryonic cells. Their studies have identified and begun to characterize a novel mechanosensitive anion channel.
C. elegans is the first metazoan organism for which the genome has been fully sequenced. The relative simplicity of the molecular and genetic techniques developed to study this organism make it an extremely powerful model system for molecular identification and characterization of ion channels and associated regulatory proteins. By combining molecular biology techniques, genetic analysis, and electrophysiologic measurements, Dr. Strange and his co-workers hope to identify for the first time the molecular components of a native eukaryotic mechanosensitive ion channel, to elucidate its role in cell function, and to define how the channel feels mechanical force.
Neurobehavioral and Psychosocial
Nutrition, Physical Fitness, and
These studies of integrated human function, or of integrated
human function deduced from well-characterized animal models,
are part of a continuum where faculty at Vanderbilt seek to define
molecular, cellular, organ, and integrative responses and their
mechanistic relationships. In fact, two Nobel Laureates from
Vanderbilt University have worked in the area of cellular regulation.
Earl Sutherland, the discoverer of cAMP as a cellular second
messenger set the paradigm for "molecular telepathy"
as a means for physiological regulation. Stan Cohen, the second
Nobelist, has an active research program in the Vanderbilt Department
of Biochemistry exploring the impact of growth factors on the
development and maintained differentiated function of cells.
This heritage of extraordinary talent in the area of cellular
function and modulation of that function should serve as an important
source of new insights for compensatory mechanisms needed to
maximize human performance in space. In addition, what is learned
about integrated physiology and counter regulation measures can
immediately be evaluated in the context of altered environments.
The NIH-sponsored General Clinical Research Center can be used
to tightly regulate diet and activity, precise minute-to-minute
measurements of metabolic expenditure can be made in the Vanderbilt
University Katahn Calorimetry Chamber, and Vanderbilt's Radiation
Oncology research program can explore the impact of varying radiation
environments on fundamental cellular processes.
Smart Systems for Health Care
Delivery with Integrated Decision Support
David Robertson, M.D. is Professor of Medicine, Pharmacology, and Neurology and Director of the Center for Space Physiology and Medicine. He also directs Vanderbilt University's General Clinical Research Center, the Division of Movement Disorders, and the Medical Scientist Training Program. He was educated at Vanderbilt and Johns Hopkins. Dr. Robertson's efforts over the past 25 years have been primarily research and teaching. In recent years, he has investigated the etiology of autonomic disorders and identified previously unrecognized genetic diseases such as dopamine-beta-hydroxylase deficiency and norepinephrine transporter deficiency. He introduced dihydroxyphenylserine as a specific treatment for DBH deficiency and methyldopa for NET deficiency. Dr. Robertson has also introduced a number of agents into the treatment of other autonomic disorders, including clonidine, yohimbine, and caffeine. In 1993, he characterized the clinical spectrum of the previously poorly understood syndrome, baroreflex failure. Dr. Robertson serves on the Space Station Human Resource Facility Committee of NASA.
F. Andrew Gaffney, M.D. is Associate Director of the Center for Space Physiology and Medicine and Professor of Medicine. Dr. Gaffney's central interest is the elucidation of interactions between body fluid distribution and neurohumoral regulatory mechanisms of cardiovascular control. He has made original contributions to the study of hemodynamic and neuroendocrine mechanisms of essential hypertension and has defined the systemic hemodynamic effects of vasoactive intestinal peptide. He was the first to show that myocardial ischemia was not a cause of the chest pain in mitral valve prolapse syndrome. He then further characterized the regulatory abnormalities in mitral valve prolapse and showed that clonidine is an effective therapeutic agent. His recent studies have addressed mechanisms of orthostatic hypotension, especially those associated with exposure to the microgravity of space. He has shown that redistribution of body fluids rather than inactivity is the cause of deconditioning. He demonstrated that the relative hypovolemia and dehydration induced by bedrest has no effect on the disposal of infused fluid, suggesting that microgravity produces a new set point for the mechanisms controlling intravascular volume and cardiac filling pressures. Since 1984, Dr. Gaffney has been heavily involved in the space program. As a payload specialist on the Spacelab Life Sciences I Mission, Dr. Gaffney went into space with a central venous catheter in place, providing the first critical invasive data on cardiovascular effects of weightlessness. His expertise in medical aspects of space flight resulted in his membership on the subcommittee for Space Biology and Medicine of the National Academy of Sciences.
Italo Biaggioni, M.D. is Associate Professor of Medicine and Pharmacology and Associate Director of Vanderbilt's General Clinical Research Center. Educated in Lima, Peru and at Vanderbilt University, Dr. Biaggioni has become a widely recognized authority on adenosine and caffeine and their influence on neurocardiovascular control. In a series of investigations in the late 1980's, Dr. Biaggioni demonstrated that adenosine exerted widespread effects on sympathetic outflow. These and subsequent investigations have required a reevaluation of the manner in which sketetal muscle afferent input into the central nervous system is mediated. In 1992, he described a previously unrecognized disorder which appears to be due to functional failure of tyrosine hydroxylase in sympathetic nerves.
Jerry Collins, Ph.D. has been active in modeling biological systems for twenty-five years. Over half of his 150 publications develop or use quantitative models. Modeling applications areas include respiratory heat and water conservation; systemic cardiovascular response to whole-body accelerations; myocardial mechanics; coronary circulatory responses to ischemia; coronary and pulmonary capillary transport responses; drug-assisted salvage of ischemic myocardium; pharmacokinetics of the metabolism of histamine blockers; characterization of linear and saturable gastrointestinal transport processes; linear, nonlinear, and fractal characterization of autonomic control of heart rate in normal and autonomically dysfunctional subjects; indistinguishability and identifiability analysis of compartmental models; compartmental analysis of the metabolism of L-dopa; and description of amino acid metabolism. He has developed many of these models himself and has also used SAAM, MLAB, SIMCON, and transport models written by others. In addition to his collaborative research with other CSPM and CRC investigators and his work as computer systems manager of the Vanderbilt University General Clinical Research Center and as Director of Computers and Biostatistics in the Clinical Research Center at Meharry Medical College, he currently serves on the editorial board of the Modeling in Physiology section of the American Journal of Physiology and is a consultant to the NIH-funded Resource Facility for Kinetic Analysis.
Roy L. DeHart, M.D., M.P.H. serves as Director of the Vanderbilt Center for Occupational and Environmental Medicine. Dr. DeHart, while serving as a medical officer in the Air Force, completed his specialty training in Aerospace Medicine. In his assignment as Chief of Aerospace Medicine for Air Force Systems Command, Dr. DeHart maintained an active role with the National Aviation and Space Administration (NASA). He served as a medical monitor of manned space flights as well as on a number of research panels addressing future manned space operations. As a senior Aerospace Medical Officer he commanded the Air Force's Aerospace Medical Research Laboratory at Wright Patterson Air Force Base, Ohio for four years. This was followed by his final assignment as Commander of the United States Air Force School of Aerospace Medicine. While in the Air Force he conducted research in radiation biology, hyperbaric medicine and potential adverse health effects due to offgassing of materials in hypobaric environments. After twenty-three years in the Air Force he entered the field of Occupational Medicine and became interested in the phenomena known as Multiple Chemical Sensitivity. He continued his relationships with NASA as a consultant in toxicology issues and medical standards for crew selection. He became an Aviation Medical Examiner for the Federal Aviation Administration (FAA) and continues to see both private and commercial pilots for their medical certification. In 1983 he joined the faculty at the University of Oklahoma College of Medicine and established a residency program in Occupational Medicine while continuing his aviation medical interests. In 1994 he was selected as Chair of the Department of Occupational and Environmental Medicine and remained in that capacity until joining the faculty at Vanderbilt University School of Medicine as Director of the Vanderbilt Center for Occupational and Environmental Medicine. Dr. DeHart is the editor of the first two editions of the textbook Fundamentals of Aerospace Medicine which has been described by reviewers as the premier text in the discipline. Preparation has begun on the third edition.
Wolf-Dietrich Dettbarn, M.D. received a degree in 1953 from the University of Goettingen in Germany. After one year of internship at Goettingen and another year at the Biology Department of the CIBA Company in Basel, Switzerland, he joined the Physiological Institute of the University of the Saarland, Germany to receive training in electrophysiology for three years. He then joined the Department of Neurology at the College of Physicians and Surgeons, Columbia University in New York where he received training in neurochemistry and did extensive research in the role of the acetylcholine system in excitable membranes such as nerve and muscle. After 10 years he was appointed Professor of Pharmacology at the Department of Pharmacology, Vanderbilt University. His research is directed towards function and dysfunction of the neuromuscular junction, control mechanisms that determine and regulate neuromuscular enzymes and morphology of muscle. Approaches used are electrophysiology, toxicology, and morphology.
Andrew C. Ertl, Ph.D. is a NASA Space Biology Reasearch Associate in the Division of Cardiology at Vanderbilt University. He received his Ph.D. in Physiology from the University of California at Davis, and performed his dissertation work at NASA Ames Research Center, Moffett Field, California. His interests include autonomic control of blood pressure, exercise countermeasures for bed rest and spaceflight deconditioning, and the effects of posture, pharmacology, and acute and chronic exercise on vascular volumes. As an NIH Research Fellow at Vanderbilt with Dr. Rose Marie Robertson and investigators at Johnson Space Center, he helped define the pharmacokinetics and pharmacodynamics of fludrocortisone, a synthetic mineralocorticoid, in subjects during the simulated microgravity of head-down tilt bed rest. A dosage regimen of fludrocortisone was developed to restore and maintain intravascular volume under these conditions. A current investigation with Dr. Rogelio Mosqueda-Garcia is the evaluation of a novel method of simulating microgravity. A pharmacological intervention will be used to reduce sympathetic activity during head-down tilt bed rest and draw comparisons to effects of microgravity on autonomic control of blood pressure. He has a continuing association with NASA Ames and the study of exercise countermeasures to bed rest deconditioning. He is participating in studies of supine treadmill exercise combined with lower body negative pressure, working with Drs. Alan Hargens and Donald Watenpaugh at NASA Ames, and Dr. David Robertson. Proposed research includes studying the effect of simulated microgravity on muscle afferents. He is a co-investigator in Vanderbilt's Neurolab Spacelab-Life Sciences Space Shuttle mission studies.
Gerald Fenichel, M.D. is Professor and Chairman of the Department of Neurology. His research interest is in neuromuscular disease. He has served as Director of the Jerry Lewis Neuromuscular Center at Vanderbilt. He is or has been on the editorial board of seven national neurology journals, the president of two national neurology societies, and an officer of two others, and a member of the Medical Advisory Board of the Muscular Dystrophy Association. Dr. Fenichel has published 83 articles in peer-reviewed journals and is the author of 49 books, book chapters, and invited reviews. His recent book on pediatric neurology is rapidly becoming the standard teaching text for this discipline.
Arthur C. Fleischer, M.D. is the Chief of Diagnostic Sonogrophy (ultrasound) at VUMC, Professor of Radiology and Radiological Sciences and Professor of Obstetrics and Gynecology. Currently he is enrolled in the graduate distance program offered by the Olegard School of Aerospace Studies at University of North Dakota. His expertise is in the use of Diagnostic Ultrasound for long duration spaceflight. This includes evaluation of musculoskeletal disorders and bone changes that occur during long duration spaceflight. He is a consultant to ATL/Phillips whose scanner has been reconfigured to be incorporated in the Human Research Module of the International Space Station.
David E. Hansen, M.D., Associate Professor of Medicine and Director of the Ventricular Laboratory, is a recognized authority on ventricular mechanics. He has made seminal contributions regarding the importance of the mitral apparatus in global and regional systolic performance of the left ventricle. Dr. Hansen's investigations in patients with surgically implanted myocardial markers provide the first comprehensive description of ventricular torsion and the mechanics of ventricular contraction. In his ventricular physiology laboratory, he utilizes sophisticated biomedical engineering approaches to control ventricular filling and ejection patterns in the isolated heart. His work represents a major breakthrough in our understanding of mechanisms of arrhythmogenesis, focusing on the stretch-activated channel hypothesis. This work on the electrophysiologic consequences of myocardial stretch and altered ventricular loading has resulted in important collaborations with investigators from the Electrophysiology Group.
Tadashi Inagami, Ph.D. has devoted his career for the last 20 years to cardiovascular research. His major accomplishments include complete purification of renin (human, pig, rat and mouse), determination of its structure, demonstration of the generation of angiotensin II by intracellular renin action, cloning of the cDNA of its precursor. For these important accomplishments in vasoactive peptides he was awarded the Ciba Award of the High Blood Pressure Research Council of the American Heart Association in 1985, the SPA Award of the Belgium National Foundation for Scientific Research in 1986, the Sutherland Award from Vanderbilt University in 1991, the Bumpus Lectureship of the High Blood Pressure Research Council of the American Heart Association in 1994, the Research Achievement Award of the American Heart Association in 1994, and the Okamoto Award of the Japan Vascular Diseases Research Foundation in 1995. He was also awarded the U.S. Senior Scientist Visiting Professorship Awards from Humbolt Stiftung, The University of Heidelberg in 1981, and the Roche Foundation Award for Visiting Professor from the University of Zurich in 1980. Dr. Inagami has been the Director of the NHLBI sponsored Specialized Center of Research in Hypertension program at Vanderbilt for the last 15 years, successfully competing for three renewals of the program.
Sanford B. Krantz, M.D., Professor of Medicine at Vanderbilt University and Chief of Hematology at the Veteran's Administration Medical Center, is well known for his studies on the application of erythropoietin (Epo) physiology to clinical disease. He discovered that pure red cell aplasia (PRCA) was caused by an autoimmune process rather than an insufficiency of Epo. Dr. Krantz has subsequently studied the anemia of chronic disorders and defined the interactions of tumor necrosis factor (TNF), interleukin-1 (IL-1), and interferon that cause the anemia. He developed a method for purifying human erythroid progenitor cells called the colony forming units-erythroid (CFU-E) and burst forming units-erythroid (BFU-E) and showed that the interferon was inhibitory to CFU-E development, resulting in the anemia. He showed in vitro that this inhibition could be overcome by the addition of Epo. Dr. Krantz also demonstrated that the anemia of chronic disease in human beings, which occurs in rheumatoid arthritis, could be completely overcome by the administration of Epo to these patients. Since then it has been shown that Epo overcomes the anemia of malignancy as well as the anemia of inflammation. Currently, Dr. Krantz is studying the pathogenesis of polycythemia vera in which patients make too many red cells and has found a hypersensitivity to IL-3 and stem cell factor (SCF). In addition, he is further studying the effect of Epo and granulocyte-colony-stimulating factor (G-CSF) on reducing the transfusion requirement and increasing white cell and red cell production in patients with a preleukemic state called myelodysplasia.
Patrick Lavin, M.B., B.Ch. is Associate Professor of Neurology and Ophthalmology and Director of the Ocular Motility Laboratory. He was educated at University College of Dublin, Leicester Royal Infirmary, and Charing Cross Hospital. He joined the faculty at Vanderbilt University in 1983. His major work has been in the anatomy and physiology of the eye movement system with particular emphasis on nystagmus. He pioneered prism therapy to improve visual acuity and suppress oscillopia in acquired nystagmus. A consummate clinician, Dr. Lavin has described a number of novel clinical signs, and is involved in taxonomy of neuro-ophthalmic disease and issues of ethics in the practice of medicine at the local, national, and international level. Dr. Lavin's expertise in clinical neurovestibular neuroscience makes him a valuable co-investigator for the Center.
Jane H. Park, Ph.D. is Professor of Molecular Physiology and Biophysics. She obtained her Ph.D. in Biochemistry from Washington University Medical School in St. Louis where she received training in the mechanism and control of enzyme action. Thereafter her work centered on the metabolic production of high energy phosphate compounds required for muscular contraction and endurance performance. More recently she has conducted investigations with elite marathon runners as well as patients with neuromuscular diseases using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). With this technology, morphological and biochemical parameters of muscle function and dysfunction are correlated during active contraction and recovery periods.
Rose Marie Robertson, M.D. is Professor of Medicine and Vice Chair of the Department of Medicine and Associate Director of the Division of Cardiology. She has been interested in cardiovascular control throughout her career. Her early studies focused on the coronary circulation and coronary artery spasm. She demonstrated that increased sympathetic activity, platelet aggregation and thromboxane release are secondary phenomena rather than etiologic in coronary artery spasm. Her subsequent studies in a porcine model of diet-induced atherosclerosis and an ovine model of LDL receptor-deficiency atherosclerosis demonstrated that endothelial abnormalities are important in enhancing in vivo and in vitro vascular tone and are the site for biogenic amine-induced spasm. She also demonstrated that minimal depolarization markedly potentiates vascular smooth muscle contraction to norepinephrine and histamine and that the inhibitory potency of calcium channel blockers is significantly enhanced in depolarized vascular smooth muscle. Dr. Robertson's studies of autonomic control of the circulation, in collaboration with Drs. Italo Biaggioni, Rogelio Mosqueda-Garcia and David Robertson, have used physiologic testing, pharmacological probes and biochemical assay methodology to define the site and severity of defects in patients with autonomic dysfunction, to determine normal autonomic responses to dietary and physiologic stimuli, and to develop improved therapies for both autonomic dysfunction and hypertension. She is currently serving the National Institutes of Health on the Cardiorenal Study Section. She is the Principal Investigator of a major NIH-supported clinical trial of dietary manipulation of sodium and calcium in essential hypertension and of the training grant in cardiovascular diseases.
Dan M. Roden, M.D. earned his degree at McGill University in Montreal in 1974. His postdoctoral training included internship and residency in Internal Medicine at the Royal Victoria Hospital in Montreal, and he came to Vanderbilt in 1978 as a postdoctoral fellow in Clinical Pharmacology and Cardiology (1978-81). He joined the faculty as Assistant Professor of Medicine and Pharmacology in 1981 and is now professor of Medicine and Pharmacology. Dr. Roden assumed Directorship of the Division of Clinical Pharmacology in January 1992. Dr. Roden's primary research interest is the pharmacology of antiarrhythmic drugs. He is involved both in the clinical care of patients with arrhythmias, as well as studies of the mechanisms of drug action which are being pursued in animal models, in isolated tissues, and in single cells.
Kevin Strange, Ph.D. is Professor of Anesthesiology and Pharmacology, and Director of the Anesthesiology Research Division. Dr. Strange received his B.S. and M.A. in Zoology from the University of California at Davis, and his Ph.D. in Zoology in 1983 from the University of British Columbia. From 1983-1986, he was a postdoctoral fellow at the National Institutes of Health. Prior to arriving at Vanderbilt in 1997, Dr. Strange was Assistant and Associate Professor of Medicine and Anesthesiology, and Director of the Critical Care Research Laboratories at Childrens Hospital and Harvard Medical School. His research interests since he was an undergraduate have focused on the physiology and regulation of membrane ion channels and transporters. Dr. Strange is widely viewed as one of the leading experts in the field of cellular fluid transport and balance. He has published over 65 peer-reviewed and invited review articles on this topic, and he edited one of the most widely cited books on cellular volume homeostasis. His research has been funded by the National Institutes of Health, the National Science Foundation, the American Heart Association, the American Diabetes Association and the National Kidney Foundation. Dr. Strange serves on the editorial boards of the American Journal of Physiology and Physiological Genomics. He was recently appointed Associate Editor of the Cell Physiology Section of the American Journal of Physiology.
Alvin M. Strauss, Ph.D., Professor and Chairman of Vanderbilt's Department of Mechanical Engineering, was educated at Hunter College and West Virginia University. Prior to assuming his current role at Vanderbilt University, he served as Head of the Department of Engineering Science at the University of Cincinnati and was Director of the Division of Mechanical Engineering and Applied Mechanics at the National Science Foundation. He is Director of the NASA Tennessee Space Grant Consortium and also serves as Chairman of the Office of Naval Research Graduate Fellowship Committee. His current research activities include NASA supported work on the biomechanics of space suit design. He continues to work on the effects of microgravity on human growth and form.
Ming Sun, Ph.D..is an Assistant Professor in the Department of Pediatrics. While studying electrical and biomedical engineering in China, he was awarded various honors for academic excellence and for his work in computer-controlled automatic drug delivery. Dr. Sun received his Ph.D. in biomedical engineering from Vanderbilt and has been the recipient of two Young Investigator Awards. His research interests include energy expenditure and work measurements in humans and animals, and the relationship between energy expenditure and body weight regulation. Dr. Sun currently serves as the director of the Energy Balance Laboratory fo the Clinical Nutrition Research Unit.
Masaaki Tamura, D.V.M., Ph.D. is a Research Assistant Professor in the Department of Biochemistry. He has been studying the molecular mechanism underlying essential hypertension by purifying and identifying the functional role of Na+, K+-ATPase inhibitors (such as cardiac glycosides) in the adrenal gland. He has recently identified the involvement of cardiac glycosides in aldosterone release from adrenal glomerulosa cells. He also studies the regulatory mechanism of cardiac glycosides in catecholamine production and release from adrenal medulla in conjunction with the local renin-angiotensin system. Determination of regulatory mechanism of catecholamine release will help to elucidate the mechanism for orthostatic hypotension and may clarify the cause of altered body fluid balance in space. Dr. Tamura presented his recent work as an invited speaker at the 2nd International Congress of Pathophysiology held in Japan in November 1994. Dr. Tamura currently serves as the director of the Protein Chemistry Laboratory for the Department of Biochemistry, the Cancer Center, and the Reproductive Biology Center at Vanderbilt University.
Taylor G. Wang, Ph.D. is Centennial Professor of Materials Science and Engineering and Director of the Center for Microgravity Research and Applications at Vanderbilt University. Dr. Wang received his doctorate in physics from the University of California at Los Angeles in 1971, and from 1972 to 1988 he conducted research at the California Institute of Technology's Jet Propulsion Laboratory. In 1983, he was selected by NASA to train as an astronaut-scientist for Spacelab-3, a research facility flown in the cargo bay of the space shuttle. In 1985, Dr. Wang flew aboard the Challenger on the successful STS-51 mission. During the flight, he studied the dynamic behavior of rotating spheroids in zero gravity in an experimental facility which he designed called the Drop Dynamics Module (DDM). Dr. Wang is currently the Principal Investigator for research projects involving drop bubble dynamics, collision and coalescence of drops, charged drop dynamics, containerless science, and encapsulation of living cells. One of Dr. Wang's experiments was chosen to be flown during the summer of 1993 as part of the first shuttle mission dedicated solely to microgravity studies. Dr. Wang is the holder of over 20 U.S. patents and author of approximately 160 articles in open literature. He is a member of the Association of Space Explorers-International, an organization of space flight crew members who promote public awareness of space flight's importance to our future. He is the recipient of the NASA Exceptional Scientific Achievement Medal, the NASA Space Flight Medal, the Chinese Insititute of Engineers Outstanding Accomplishment Award, and the Taylor G. Wang Recognition Day in Washington, D.C.
Grant R. Wilkinson, Ph.D. is currently Professor of Pharmacology and Associate Director for the Clincal Pharmacology Center at Vanderbilt University. He received his B. Sc. in Pharmacy from the University of Manchester and his Ph.D. from the University of London. From 1966-68 he spent a postdoctoral fellowship at the University of San Francisco and then joined the faculty of the College of Pharmacy at the University of Kentucky as an assistant professor. Three years later he moved to Vanderbilt and has been there for the last 21 years. Dr. Wilkinson is a Fellow of the American Association for the Advancement of Science and was also elected to fellow membership in the Academy of Pharmaceutical Sciences. He serves on the editorial advisory boards of several journals including being a field editor for drug metabolism and disposition for the Journal of Pharmacology and Therapeutics. Dr. Wilkinson's major research interests and many published contributions have been in the broad area of drug disposition, particularly the elucidation of factors determining interindividual differences in drug responsiveness.
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