CAM Research Training in Neuroscience and Stress

The Oregon Center for Complementary and Alternative Medicine in Neurological Disorders is an T32 institutional training grant, CAM Research Training in Neuroscience and Stress, from the National Center for Complementary and Alternative Medicine at NIH. Dr. Barry Oken is the director of the training grant. This training grant provides funding for predoctoral students in the Behavioral Neuroscience Department at Oregon Health & Science University (OHSU) and for postdoctoral fellows with an interest in complementary medicine and either neurology or stress, including oxidative/nitrative and toxicologic stress. Complementary medicine is a broad area and includes treatments such as dietary supplements and mind-body medicine as well as others (see http://nccam.nih.gov/health/whatiscam/ for fuller description of CAM).

Predoctoral positions

The predoctoral positions are awarded to PhD students in the Behavioral Neuroscience Department at OHSU. More details of the Behavioral Neuroscience graduate program may be found at http://www.ohsu.edu/behneuro/graduate/index.htm. Students need to apply to the PhD program using the routine application procedure. During the first year, if they choose to work with a mentor on a project of relevance to CAM, then they will apply for the T32 training grant support. This entails a proposal for the planned research, mentor support letter, and interviews with several seniors members of the training grant. For some projects, dual mentors would be required. This depends on whether the primary mentor has significant CAM research experience or whether a second mentor would be needed to provide that expertise.

Post-doctoral fellowship positions

The post-doctoral fellowships will be for two years with the possibility of extending them depending on the fellow’s success and funding availability. Fellows conducting clinical research will be expected to participate in the Human Investigations Program at OHSU (http://www.ohsu.edu/dmice/hip/). Fellows will be primarily located at either OHSU or the Linus Pauling Institute at Oregon State University. Collaborative opportunities are also available with Western States Chiropractic College, the National College of Naturopathic Medicine and the Oregon College of Oriental Medicine. All potential mentors will be listed at http://www.ohsu.edu/orccamind/, although some of the mentors may only be able to act as a co-mentor, depending on their experience in mentorship and research.

Eligibility: Applicants must have a PhD, MD, DC, ND or other doctoral degree and be a US citizen or have been lawfully admitted for permanent residence.

Application process: After contacting potential mentors, applicants should send a letter of interest expressing what they would like to accomplish over the fellowship-training period. This may include a description of potential research areas and preferred faculty mentor(s). The applicant should also describe their long-term career interests and how this post-doctoral fellowship will help them. The letter of interest, CV, and 3 letters of recommendation should be sent to: Dr. Barry Oken, Oregon Health & Science University, CR-120, 3181 SW Sam Jackson Park Rd, Portland, OR 97239.

Mentors List

All applicants must select a mentor from the following list. Primary mentors must have a significant history of prior mentorship and of CAM research. If the mentor selected does not have this level of experience in both areas, a co-mentor with primary experience in the other area that is lacking will also need to be established.

Bruce Bebo, Ph.D., Neurological Sciences Institute, OHSU. The disease-modifying effect of steroidal estrogens in multiple sclerosis (MS) has the potential to be more potent than currently available treatments for this disease. However, it is likely that prolonged treatment with steroidal estrogens would be required to sustain a clinical benefit. Prolonged treatment of MS patients with steroidal estrogens carries with it significant risks for the development of hormone-related cancers that would, in most cases, outweigh the benefits. Therefore, the Bebo laboratory is studying the therapeutic effects of naturally occurring phytoestrogens in an animal model of MS. The lab has found that mice fed diets rich in soy isoflavones are protected from an MS-like disease. Whether phytoestrogens regulate myelin-specific immune responses is a major question the laboratory is currently trying to answer.

Joe Beckman, Ph.D., Linus Pauling Institute, OSU. The Beckman lab investigates the dark side of nitric oxide – how nitric oxide interacts with superoxide (O2.-) and other radicals to form much stronger oxidants such as peroxynitrite (ONOO-) and how peroxynitrite modulates signal transduction. We developed antibodies to nitrotyrosine, which is now a widely used marker for the role of nitric oxide-derived oxidants, particularly peroxynitrite, in biology and pathology. A major interest in the lab is to understand how mutations to the copper, zinc superoxide dismutase (SOD) gene can cause Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis. The lab is currently investigating the role of zinc in protecting transgenic mice against the toxicity of ALS-mutant SOD. The Beckman lab is also investigating the effects of a common pesticide, metam sodium, on cell function. This is closely related to a common inhibitor of Cu,Zn superoxide dismutase and may also affect activation of NFkB.

Dennis Bourdette, M.D., Neurology Department, OHSU. Dr. Bourdette is Chair of the Department of Neurology at OHSU as well as a staff neurologist at the Portland VA Medical Center. He is also Director of the Multiple Sclerosis (MS) Center of Oregon and co-Director of the MS Center for Excellence-West located at the Portland VA Medical Center. His area of special interest is the immunopathogenesis and treatment of multiple sclerosis and other neuroimmunologic diseases. His NCCAM funded research through ORCCAMIND involved evaluating the effect of several natural antioxidants on a mouse MS model. The finding that alpha lipoic acid produces significant clinical improvement in the mouse by inhibiting T-cell migration into the CNS has resulted in significant follow-up research including an ongoing clinical trial. Other current CAM-related research includes a clinical trial of ginkgo biloba on cognitive function in MS and assessing several botanicals for their effect on neurite growth in vitro.

Carlo Calabrese, ND, MPH, National College of Naturopathic Medicine. Dr. Calabrese is a Senior Investigator at the Helfgott Research Institute and Research Professor at National College of Naturopathic Medicine (NCNM), and works in developing research methods for investigating complementary and alternative medicine (CAM). He has performed and published clinical trials and observational studies in nutrients, botanicals, and CAM practices. Dr. Calabrese was an investigator in ORCCAMIND, being a member of the Executive Committee and carrying out a pilot trial of bacopa on cognitive function in seniors. He was also past of the Kaiser Permanente Center for Health Research NCCAM P50 Oregon Center for CAM. He serves on the NIH NCCAM Data and Safety Monitoring Board and has recently been appointed to the Advisory Council of NCCAM. He was a founder and Co-director of the Bastyr University Research Institute and taught epidemiology and biostatistics at Bastyr. He authored one of the first successful applications for an NIH research grant to a CAM institution and contributed to the development of ethical research oversight and laboratory facilities at both Bastyr and NCNM. He is currently a principal in the development of a national research agenda for naturopathic medicine and working on clinical trials in a variety of conditions.

Wayne Clark, M.D., Oregon Stroke Center, OHSU. The Oregon Stroke center is a leading national center in acute stroke treatment and clinical stroke research. The center has three stroke Neurologists, one current stroke fellow, two interventional Neuroradiologists, two Neurosurgeons, four nurse coordinators, and five research coordinators. Over 20 NIH and industry sponsored stroke treatment and prevention clinical trials are in progress. CAM therapies are an important part of both our clinical practice and our research focus. Our patients are routinely offered acupuncture (Oriental College of Medicine) for pain and contraction. We also frequently suggest the use of supplements on selected cases such as: stroke recovery- CDP choline; memory CDP- choline or ginkgo biloba; cholesterol- Teaflavins; vision- bilberry. We are currently submitting a R21 NCCAM grant to evaluate the tea flavonoids in preventing carotid stent restenosis. We also have an active research lab focusing on the abilities of natural supplements to reduce neurologic stroke injury in experimental stroke models. This includes an ongoing R21 funded NCCAM/NINDS “ Evaluation of Ginkgo Biloba in the Treatment of CNS Ischemia” and a current project (part of P50) submission “ Evaluation of Grape Seed Extract Therapy in Focal CNS Ischemia.

Christopher Cunningham, Ph.D, Behavioral Neuroscience Department OHSU. This lab is generally concerned with motivational effects of abused drugs, with special emphasis on genetic and brain mechanisms underlying drug-seeking and drug-taking behavior. These studies involve various animal genetic models, including selectively bred mouse lines, recombinant inbred strains, congenic strains, and knockout/transgenic strains. Behavioral procedures commonly used include: operant self-administration, place conditioning (preference and aversion), and taste conditioning. In some projects, studies are designed to identify and characterize the physiological, neuroanatomical, neurochemical and molecular systems that mediate drug reward and aversion. These studies may involve systemic or intracranial administration of pharmacological agents (e.g., receptor agonists or antagonists). Other studies, done in collaboration with OHSU faculty colleagues, examine molecular changes produced by drug exposure. The lab is also engaged in projects that examine the roles played by environment, experience and learning. Of special relevance to this training program are studies that address the role of Pavlovian conditioning and other cognitive processes on the response to drugs, including “placebo” responses. For example, in a recent collaborative project with Drs. Richard Jones, Barry Oken and Dennis Bourdette, the beneficial impact of Pavlovian conditioning on the therapeutic response to ALA (alpha lipoic acid, thioctic acid) in mice with paralytic autoimmune encephalomyelitis (EAE) has been examined.

Frei, Balz, Ph.D., Linus Pauling Institute, OSU. The research program in the Frei laboratory is aimed at understanding the mechanisms of oxidative stress in human disease, in particular atherosclerosis, and the ameliorating effects of dietary and metabolic antioxidants, dietary supplements, and metal chelators. One of the earliest events in atherosclerosis is endothelial dysfunction with increased expression of adhesion molecules and monocyte chemoattractants. As a consequence, monocytes are recruited to the arterial wall, where they initiate an inflammatory response and give rise to lipid-laden foam cells. The lab is performing biochemical, cell biological, and animal studies to investigate the mechanisms and consequences of endothelial dysfunction, the role of pro-oxidant transition metals like iron and copper in this process, and the effectiveness of ascorbic acid, lipoic acid, and other antioxidants in ameliorating endothelial dysfunction. Recent work in the Frei laboratory has shown that metal chelators and lipoic acid, but not ascorbic acid or glutathione, can inhibit the expression of adhesion molecules and monocyte chemoattractant peptide-1 in human aortic endothelial cells. The lab is now studying the cellular mechanisms underlying these beneficial effects on endothelial function, in particular inhibition of redox-sensitive cell signaling and transcription factors (NFB, Sp-1, and AP-1). In addition, the lab is studying whether metal chelators and lipoic acid can exert anti-inflammatory and anti-atherogenic effects in transgenic mouse models by inhibiting adhesion molecule and MCP-1 expression. These studies will also address the question of whether chelation therapy with EDTA or desferrioxamine (Deferal®), currently used in CAM, is safe and efficacious in inhibiting atherosclerosis. The interdisciplinary nature of our studies results in collaborations with Drs. Hagen and Beckman, who are investigating the role of lipoic acid, metal chelators, and other “CAM antioxidants” in aging and amyotrophic lateral sclerosis, respectively. The ultimate goal of these collaborative studies, which are funded by a NCCAM program project grant, is to provide the essential knowledge about the underlying mechanisms, dose-response effects, and relevant biological targets to advance these CAM therapies to human trials; and, equally important, to test for untoward effects that might discourage CAM antioxidant therapies from proceeding to human studies.

Mitchell Haas, DC, Western States Chiropractic College. Dr. Haas has collaborated with Dr. Oken in mind-body medicine as a co-investigator on the yoga study in ORCCAMIND and through a pilot trial that included a placebo model for immediate pain relief following spinal manipulation. He is co-investigator in Dr. Oken’s U19 application to study expectancy and a R01 proposal to study stress reduction with mindfulness meditation for caregivers of Alzheimer’s disease patients. Dr. Haas has further been a PI on a study of self-management of back pain in the elderly, including evaluation of the effect of improved self-efficacy on back pain (R18 HP10012). He has extensive research experience in chiropractic management of pain and diagnostic procedures for determining manipulative therapy.

Hagen, Tory, Ph.D., Linus Pauling Institute, OSU. The Hagen lab investigates two interrelated and fundamental aspects of aging: 1) the causes and consequences of mitochondrial decay in cardiovascular aging, and 2) the mechanisms associated with loss of oxidative stress resistance in the elderly. Moreover, the lab seeks to identify “age-essential” micronutrients, which can improve/maintain mitochondrial function and/or increase resistance to oxidative insult. The lab has shown age-related changes in the mitochondria in the aging rat heart, brain and vascular endothelial cells in terms of reduced levels of glutathione and vitamin C, a lower thiol/disulfide ratio, heightened levels of oxidative damage and lower indices of mitochondrial bioenergetic parameters. However, dietary addition of R-a-lipoic acid (LA) reverses much of the increase in indices of oxidative stress while dietary supplementation with acetyl-L-carnitine maintains bioenergetic parameters, particularly in the aging rat brain and myocardium. With regards to altered stress resistance, the lab has shown that feeding LA to old rats reverses the age-related increased susceptibility to toxic insult (tert-butylhydroperoxide and menadione). Because LA is rapidly metabolized in the cell, we hypothesized that it may be acting as a signaling molecule to upregulate stress response mechanisms. We found that LA works by inducing the nuclear translocation of a transcription factor, Nrf2, which in turn, initiates expression of over 300 genes involved in oxidative/toxicological stress response in the cell. These findings thus have large ramifications for overall resistance to pathophysiological insult, which otherwise declines with age. These studies are in concert with those of Drs. Balz Frei and Joseph Beckman, who along with the Hagen lab, have been awarded a P01 (NCCAM) to examine antioxidants, such as LA, on cardiovascular and neurological disorders.

Hammerschlag, Richard, Ph.D., Oregon College of Oriental Medicine. The Research Department of the Oregon College of Oriental Medicine, created in November, 1999 under the direction of Dr. Hammerschlag is currently involved in five collaborative research projects assessing the clinical efficacy and mechanism of acupuncture and other modalities of Traditional Chinese Medicine. Clinical trials are focused on (1) Temporo- mandibular Disorder (TMD)-related acute pain: a 4-arm trial of Acupuncture, Chiropractic, Massage Therapy and Biomedical care in collaboration with Kaiser Center for Health Research; (2) Chronic TMD: a 3-arm trial of Traditional Chinese Medicine, Naturopathic Medicine and Biomedical care, also based at Kaiser CHR; (3) Multiple Sclerosis-specific fatigue: a double-placebo trial of Acupuncture and Chinese Herbs, in collaboration with the Dept. of Neurology, Oregon Health & Science University; and (4) Endometriosis-related pelvic pain: a comparison of Traditional Chinese Medicine and Hormone Therapy, in collaboration with the ObGyn Dept, OHSU. An additional study, in collaboration with the Electrical & Computer Engineering Dept at Portland State University, focuses on the electrodermal properties of acupuncture points. All four clinical trials and the mechanism study are funded by NIH/NCCAM. Dr. Hammerschlag, the Research Director, has had experience mentoring pre and postdoctoral research fellows at the Oregon College of Oriental Medicine and during his prior 25 year career in basic neurobiological research.

Hatton, Dan, Ph.D., Behaviorial Neuroscience Department, OHSU. Dr. Hatton’s lab examines the role of mineral nutrition on energy regulation and affect. Animal models are used to examine the effects of nutrition on gene expression within the neuroendocrine pathways involved in energy regulation. This includes leptin signaling and other orexic/anorexic signals, as well as autonomic nervous system and central biogenic amine pathways. Microarrays, rtPCR, and physiological recordings are used to assess the effects of nutrition. In humans, projects include the effects of calcium supplementation on weight regulation during and following pregnancy as well as the effects of calcium supplementation on postpartum depression in women at risk for affective disorders. A number of psychometric tests are used for assessment along with psychiatric interviews, assessments of dietary intake and energy expenditure. Body composition is measured using dual x-ray absorptiometry.

Hersh, William, M.D. Medical Informatics And Clinical Epidemiology Department, OHSU. Dr. Hersh performs research in a variety of areas related to medical informatics and evidence-based medicine. His major area of focus is information retrieval, which investigates the optimal means for the production, organization, retrieval, and evaluation of scientific literature. Dr. Hersh has a great deal of experience developing retrieval systems as well as evaluating them in the hands of real users. He also has performed systematic reviews and evidence reports about telemedicine and other informatics-related topics. Dr. Hersh also has much experience with educational technologies and serves as the director of OHSU's distance learning programs in medical informatics. He directed the education and information transfer core for ORCCAMIND and has participated in the Cochrane Collaboration complementary medicine group.

Horak, Fay, Ph.D., Neurological Sciences Institute, OHSU. Dr. Horak studies neural control of posture and gait and the effects of neurological disorders in order to improve balance rehabilitation. Of particular interest are changes in postural strategies in the elderly and in patients with pathologies common in the elderly: Parkinson’s disease, cerebellar ataxia, vestibular loss, and peripheral neuropathy. Studies involve quantification of body motions, surface forces and muscle activation patterns in response to controlled perturbations of stance and gait and the ability to adapt to altered environmental conditions. Her laboratory also investigates the effectiveness of medications, surgeries and new approaches including Alexander Technique to rehabilitation on balance disorders and back pain. Dr. Horak leads a sensorimotor control journal club and lectures in a Behavioral Neuroscience course on Multisystem Understanding of Aging. Her studies have direct application to improving the diagnosis and rehabilitation of balance disorders to prevent falls in the elderly.

Hurn, Patricia, Ph.D., Anesthesiology-Research, OHSU. The lab is focused on the study of mechanisms of hormone protection from brain injury such as stroke and is part of an emerging center for research into gender biology. Because endogenous sex steroids such as estradiol have limited utility in prevention or treatment of stroke, we have an ongoing interest in phytoestrogens and other alternative therapies of hormonal basis. Studies are conducted exclusively in animal and cultured cell models of ischemic injury and incorporate a wide range of physiological, histological and molecular biological techniques.

Janowsky, Jeri, Ph.D., Behavioral Neuroscience Department, OHSU. The focus of the research in this laboratory is the brain basis of human cognition, with a particular focus on the cognitive and neural changes that occur with aging and dementia. The majority of the work concerns the role of sex hormones as modulators of cognition, particularly during aging. Current studies focus on sex differences and the effects of estrogen and testosterone replacement on emotion and emotional memory in aging. A second set of studies focus on whether testosterone affects cognition by its aromotization to estrogen. In addition to the behavioral and pharmacological techniques, this group uses quantitative and functional magnetic resonance brain imaging to study brain aging. The interdisciplinary nature of these studies results in collaborations with endocrinologists, experts in functional neuroimaging and signal processing (Drs Stevens and Song), others who study cognition in aging (Drs. Kaye, Kohama, Neuringer, Oken) and those who study stroke and functional imaging measures for stroke (Dr. Lutsep). Dr. Janowsky has an extensive track record of mentoring students and faculty including receiving OHSU’s first Outreach award for her work with high school programs to bring students to OHSU research labs and to promote programs for women in science. She has both Ph.D.and M.D. trainees in her laboratory.

Johnson, Steven, M.D, Ph.D., Neurology Department OHSU. The Johnson laboratory uses electrophysiological techniques to study the neuropharmacology dopamine in the brain. Using an animal model of Parkinson's disease, we are actively studying effects of dopamine neurodegeneration on the synaptic pharmacology of deep brain structures such as the subthalamic nucleus. Another current project investigates effects of environmental toxins, such as pesticides and herbicides, on physiological membrane properties of dopamine neurons. Other projects have investigated the actions of dietary supplements, such as gamma-hydroxybutyrate and ephedra, on dopamine neurophysiology.

Jones, Richard, Ph.D., Neurology Department, OHSU. Current efforts within this laboratory are directed towards understanding mechanisms controlling disease susceptibility, disease onset and disease progression in multiple sclerosis (MS). These mechanisms are being investigated using an established animal model of MS, rodent experimental autoimmune encephalomyelitis (EAE) and novel adaptations of this animal model. One area of emphasis is the role played by hematopoietic myelomonocytic lineage cells in controlling susceptibility to, onset of and progression of this inflammatory T lymphocyte mediated, paralytic autoimmune disease. A second area of emphasis is the role of immune status upon disease progression in a novel spontaneous disease model. A third and new area of emphasis within this laboratory is directed towards mechanisms of nervous system regulation of immune mediated CNS pathogenesis and uses a modified classical behavioral conditioning paradigm developed in this laboratory to examine integrative and associative neurobiological pathways and processes capable of creating therapeutic improvements in clinical status.

Kaye, Jeffrey, M.D., Neurology Department, OHSU. Dr. Kaye is Professor of Neurology and Director of the NIA funded Layton Aging and Alzheimer’s Disease Center at Oregon Health and Science University. Dr. Kaye’s research program has focused over the past decade on the research question of why some individuals remain protected from dementia at advanced ages while others succumb at much earlier times. In order to answer this question he has emphasized the high-risk population of people at age 85 or older (the “oldest old”). The centerpiece of these studies has been the ongoing Oregon Brain Aging Study, established in 1989. This study has made several original contributions pertaining to exceptional aging ranging from defining the role of health in delaying cognitive decline to discovery of presymptomatic markers of cognitive decline related to brain volumes, cognitive performance and genetic risk. In this context, most recently in collaboration with the Oregon Center for Complementary and Alternative Medicine in Neurological Disorders and funded by NCCAM he has been investigating the role of standardized ginkgo biloba extract in preventing dementia in cognitively intact octogenarians. This is the first such study to apply biomarkers to the study of dementia prevention. Dr. Kaye has also conducted similar studies in Alzheimer’s disease patients where he has served as a mentor to junior investigators studying CAM compounds such as cats claw and lactoferrin.

Lewy, Alfred, M.D., Ph.D., Psychiatry Department, OHSU. Bright light and melatonin research is notfunded by drug companies, because they are CAM-related treatments.Dr. Lewy's research group is interested in circadian rhythm physiology and circadian rhythm disorders. They have pioneered the use of bright light and melatonin at low, physiological doses in adjusting circadian phase position, as well as measurement of the melatonin rhythm as a marker for the endogenous circadian pacemaker. They have focused on winter depressives and totally blind people, using them as models. Winter depressives have a clear?cut disorder of circadian rhythms: most of them are phase delayed when depressed in the winter. They preferentially respond to bright light in the morning or melatonin in the afternoon, both of which provide a corrective phase advance. Most totally blind people free?run, with a period slightly longer than 24 hours. These individuals can be treated with a daily dose of melatonin that provides a corrective phase advance. Other circadian-rhythm disorders include advanced and delayed sleep phase syndromes, jet lag, shift work maladaptation and some types of non-seasonal depression. Phase-advanced disorders can be treated with evening bright light and/or morning melatonin.

Lou, Jau-Shin, M.D., Ph.D., Neurology Department, OHSU. The lab uses a variety of electrophysiologic techniques to study physiology of normal motor control and pathophysiology of Parkinson’s disease and amyotrophic lateral sclerosis. The techniques available in the lab include transcranal magnetic stimulation (TMS) (single, paired and repetitive), three-dimensional MRI-TMS co-registration of the brain, nerve conduction study, EMG, motor unit counting, multi-channel surface EMG monitoring, blink rates, force generation, fine-finger movement monitoring and tremor analysis. The lab is currently conducting a pilot study using TMS to study the effect of placebo on the cortical responses. The lab also conducts therapeutic trials using CAM interventions to treat symptoms in Parkinson’s disease and amyotrophic lateral sclerosis.

Morris, Cynthia, Ph.D., M.P.H., Medical Informatics And Clinical Epidemiology Department, OHSU. Dr. Morris is assistant dean for admissions OHSU School of Medicine and Vice-Chair of the Department of Medical Informatics and Clinical Epidemiology, with dual appointments in the Departments of Medicine and Public Health and Preventive Medicine. As an epidemiologist, she has extensive experience in clinical trials, population?based studies, patient registries, and systematic reviews. Dr. Morris has directed the Biostatistics and Study Design Core of the ORCCAMIND project, and through this, she has coordinated the major trials as well as all the smaller, developmental studies in complementary and alternative medicine. From this endeavor, Dr. Morris recently developed a new Clinical Research Data Resource at OHSU for trial coordination and the maintenance and establishment of practice networks for research. Her principal research focus has been in the etiology of congenital malformations. She established the Oregon Registry of Congenital Heart Defects, the only population-based registry of its kind in the US; she also has established a research focus on the role of folate intake and metabolism in congenital heart disease. She is a member of the Oregon Evidence-Based Practice Center, and performed the systematic review on which recommendations from the US Preventive Task Force on antioxidant supplementation for cancer and heart disease prevention are based. Dr. Morris established and directs the NIH K30 funded Human Investigations Program to train faculty in fellows in clinical research. Thus far, more than 85 faculty have enrolled in the program's first three certificate cohorts, including 6 complementary and alternative medicine practitioners from outside OHSU (National College of Naturopathic Medicine, Oregon College of Oriental Medicine). From this K30 program, Dr. Morris has recently proposed a Master of Clinical Research degree that has been approved at all level at OHSU and is now awaiting final approval by the Oregon University System for implementation in fall, 2004. Dr. Morris has a long record of mentoring physicians and medical students pursuing an MPH at OHSU; in addition, she is the primary mentor for one K23 grantee at OHSU, and is actively working with three others for K23 development. She serves on the Board of Directors of the Association of Clinical Research Training Program Directors Association.

Nutt, John, M.D., Neurology Department, OHSU. Dr. Nutt and the Movement Disorders Group focus on movement disorders with particular interest in Parkinson’s disease, gait disorders of the elderly, and experimental therapeutics of movement disorders. These interests have led to studies of coenzyme Q10 in Parkinson’s disease, effects of diet and exercise on response to levodopa in Parkinson’s disease and Kava-Kava in Huntington’s disease. Current studies examine the effects of inhibition of the dopamine transporter on the response to levodopa and the effects of infusion of glial derived neurotrophic factor (GDNF) into the striatum of patients with Parkinson’s disease.

Oken, Barry, M.D., Neurology Department, OHSU. The lab has a long history of trying to better understand the mechanisms underlying the age-related decline in human cognition, primarily visual attention, with particular emphasis on those mechanisms that may be remediable. The lab is currently studying the effects of mind-body medicine, including yoga, meditation and expectancy or placebo effects, on human cognition and physiology. Projects include both interventional as well as mechanistic studies. The current studies maintain the emphasis on aging. Human subjects for the experiments are healthy young adults, healthy older adults, and older adults with diseases neurodegenerative disorders e.g., Alzheimer’s and Parkinson's disease. Dr. Oken has a long-standing interest in human neurophysiology focusing on EEG and evoked potentials. Physiologic markers for stress are a major current interest. Assessments include experimental cognitive tasks using accuracy, reaction time, conventional clinical neuropsychologic tests, personality traits, fatigue and quality of life. Physiologic measures include conventional EEG, digital EEG signal analysis, event-related potentials, autonomic nervous system activity (e.g., heart rate variability),and scanpaths.

Quinn, Joseph, MD, Neurology Department, OHSU. Dr. Quinn's research program utilizes animal models and human "biomarker" studies for the purpose of developing strategies for prevention and treatment of Alzheimer's disease, with a focus on oxidative damage as a treatable mechanism. Anti-inflammatory and antioxidant strategies have been studied in a transgenic mouse model of AD (Tg2576), and are currently being examined in human trials employing cerebrospinal fluid disease markers. The biomarker strategy reduces the numbers of subjects necessary for "proof of concept" trials, and permits conclusions regarding the biological basis of treatment efficacy, conclusions which are not possible in traditional clinical trials based solely on cognitive outcomes. The animal model strategy also permits the screening of combination therapy, which is not practical in the clinical setting. The animal studies are currently focused on co-enzyme Q and a copper-chelating agent, with plans to explore combination therapy with agents previously proven effective, including alpha lipoic acid and ibuprofen. The focus is on agents which are already approved for use in clinical trials, so that the animal studies may be quickly translated to clinical trials.

Roselli, Charles, Ph.D., Physiology and Pharmacology Department, OHSU. The lab is studying the effects of complementary herbal medicines on neuroendocrine reproductive function and prostate cancer. Projects include both in vivo animal studies and in vitro mechanistic studies. Currently we are studying the effects of Saw Palmetto (Serenoa repens) berry extract on IGF-1 signaling pathways in human prostate cell lines. We have also assessed the effects of the prostate herbal mixture PC-SPES on the neuroendocrine axis of rats. The laboratory uses a variety of experimental techniques, including hormone evaluations, molecular and cell biological techniques to measure phosphylation states of signaling molecules, gene expression, and enzymatic activities.

Soumyanath, Amala, Ph.D., Neurology Department, OHSU. Dr. Soumyanath is a pharmacist with specialization in pharmacognosy, the scientific study of medicinal plants. Her laboratory utilizes techniques used in the authentication of plant material such as botanical microscopy and macroscopical analysis, thin-layer chromatography (TLC) and high performance liquid chromatography (HPLC), as well as their quantitative evaluation using HPLC, UV-VIS spectroscopy, and volatile oil analysis. The laboratory also uses techniques required in extraction and fractionation of plants and the isolation and structure elucidation of pure compounds from these extracts. These fractionation and isolation processes are usually interfaced with biological assays in order to home in on active compounds within the extracts. Techniques for fractionation and isolation include a range of column and planar chromatography methods with a variety of mobile and stationary phases. Identification of structures is achieved by means of mass spectrometry and nuclear magnetic resonance spectroscopy as well as UV-VIS and infrared spectroscopy. The laboratory is presently working with plants used traditionally in neurological disorders. Collaborations have been established at OHSU with Dr Joseph Quinn to study plant extracts in in vitro and in vivo models of Alzheimers disease, Dr Bruce Gold to look at neurite outgrowth in cultured neurons, Dr Siegward Elsas to study anti-epileptic plants in vitro and Dr Dennis Bourdette to study effects of plant extracts in an animal model of multiple sclerosis. In collaboration with Dr Peter Spencer, the laboratory is also working with plants from the order Cycadales which are known to contain neurotoxic agents.

Traber, Maret, Ph.D., Linus Pauling Institute, OSU. This laboratory investigates the function and bioavailability of vitamin E in humans. To define alpha-tocopherol functions at the molecular level, several tools are available. The lab uses different forms of vitamin E to test specific functions. For example, despite having identical antioxidant activities, natural and synthetic alpha-tocopherols are utilized differently, because they have different stereochemistries. The alpha-tocopherol transfer protein (TTP) in liver is critical in this regard. We have developed an alpha-TTP-knockout mouse in which the gene for this protein has been deleted. Hence, this mouse is unable to discriminate between natural and synthetic alpha-tocopherols. Plans are underway to use this mouse to define specific molecular functions and pathways that are susceptible to alpha-tocopherol deficiency. Additionally, other naturally occurring forms of vitamin E, such as gamma-tocopherol and the tocotrienols, are being investigated to assess whether they have specific roles in human nutrition. Studies of vitamin E metabolism serve to determine whether there is sufficient vitamin E in the face of oxidative stress. Preliminary data in smokers and extensive exercisers who are under increased oxidative stress suggest that oxidative stress increases the need for vitamin E. Studies of the kinetics of deuterated tocopherols in smokers compared with non-smokers, or in athletes during exercise and at rest, will allow assessment of the vitamin E requirements and their relationship to vitamin E metabolites. The availability of deuterated tocopherols has now made it possible to carry out extensive measurements of the biokinetics and bioavailability of vitamin E in humans. The Traber laboratory has developed new methodologies using liquid chromatography-mass spectrometry that are 100-fold more sensitive than previous methods. The purpose of these measurements is to detail the requirements of normal humans and those with diseases related to oxidative stress, such as atherosclerosis, cancer, diabetes and Alzheimer's disease.

T32 Executive Committee