Glen Kisby, Ph.D.
Associate Professor of Pharmacology
College of Osteopathic Medicine of the Pacific - Northwest
Phone: 541-259-0217 | Fax: 541-259-0201
Join year: 2011
Ph.D., Pharmacology/Toxicology, University of Texas, Austin, Texas, 1986
B.S., Pharmacy, Northeastern University, Boston, Massachusetts, 1980
B.A., Chemistry, Bridgewater State College, Bridgewater, Massachusetts, 1976
As Dr. Linda Birnbaum (Director of NIEHS) pointed out last year at a National Academy of Sciences (NAS) Workshop, “Exposure to gene-altering substances, particularly in the womb and shortly after birth, can lead to increased susceptibility to disease. The susceptibility persists long after the exposure is gone, even decades later. Glands, organs, and systems can be permanently altered.” Our lab has a long-standing interest in understanding the role of gene-altering substances (i.e., genotoxicants) in both neurodegenerative disease and neurodevelopment disorders. We are specifically interested in determining if the genomic dysregulation produced by environmental chemicals (e.g., carcinogens, pesticides, metals) during critical periods of brain development activates cellular processes that increase the vulnerability of the brain to neurodegenerative disease or neurodevelopmental disorders.
The genotoxicant methylazoxymethanol (MAM) is considered an important etiological factor in western Pacific ALS/PDC and it is becoming an increasingly valuable tool to probe the underlying pathophysiology of schizophrenia. The genomic dysregulation produced by MAM during critical periods of brain development could explain how this genotoxicant induces pathogenic changes like those observed in ALS/PDC or alters the normal developmental trajectory of the brain to induce features like those observed in schizophrenia. Our primary focus over the next several years (in chronological order) is to continue using rodent models of neurodegenerative disease (e.g., htau) and neurodevelopmental disorders (i.e., MAM animal model of schizophrenia), DNA repair mutant mice and the model genotoxicant MAM as tools to answer the following pivotal questions: (i) Is genomic dysregulation a key mechanism by which environmental chemicals induce the accumulation of tau and synuclein? (ii) Is genomic dysregulation an important mechanism by which MAM induces an animal model of schizophrenia? and (iii) Do genotoxicants influence brain function during early development by a mechanism involving both DNA damage and epigenetic changes? Findings from these studies are expected to lay the groundwork for understanding how the interaction between environmental and genetic factors contributes to neurodegenerative disease and neurodevelopmental disorders.
Role of Insulin Signaling in a Mouse Model of western Pacific Dementia (Alzheimer’s Association Grant).
It is becoming increasingly clear that many factors, both inherited and environmental, interact in a complex and poorly understood manner to cause dementia or Alzheimer’s disease (AD). Determining how environmental factors (e.g., exposure to a toxin) specifically interact with genetic factors (e.g., tau, DNA repair) to disrupt cellular processes that contribute to neurodegenerative disease could provide important clues about the complex mechanisms of neuropathogenesis that occur in dementia or AD.
Recent studies of a neurological disorder in the western Pacific (i.e., PDC) with features very similar to AD has provided important insight into how both environmental and genetic factors might contribute to Alzheimer-type brain injury. Sundar and colleagues (2007) recently identified two polymorphisms within the non-coding regions of the tau gene (MAPT) in individuals with PDC, changes that increase tau expression. In separate studies, Borenstein and colleagues (2007) showed that children or young adults who ate food prepared from the cycad plant, a plant that contains significant quantities of the genotoxicant cycasin, were at great risk of developing mild cognitive impairment, dementia or PDC. These studies strongly suggest that early life exposure to cycasin (the glucoside of MAM) and the inherent dysregulation of tau are two important factors that contributed to the tau pathology in PDC. In strong support of this hypothesis, MAM induced DNA damage (i.e., O6-mG lesions), altered tau metabolism and accelerated tau pathology in an animal model of PDC (i.e., htau mouse). MAM also altered enzymes that regulate the phosphorylation (i.e., GSK3) and truncation of tau (i.e, caspases) in htau mice. More recently, genomic studies of the murine brain showed that the O6-mG DNA lesions produced by MAM were specifically linked to genes that regulate several cell-signaling pathways (e.g., insulin, Wnt, P38-MAPK) (Kisby et al., PloS One). These recent findings suggest that cycads contribute to the tau pathology in PDC by inducing DNA damage and perturbing specific cell signaling pathways during brain development. Since the diabetogenic agent streptozotocin induces brain insulin dysfunction, tau pathology and alkylates DNA like MAM, future studies are planned to determine if MAM works by a similar mechanism to accelerate the tau pathology in htau mice. If our hypothesis is correct, the increased tau expression and the insulin resistance produced by early life exposure to cycads might be important genetic and environmental factors that initiated the neuropathology and cognitive deficits in individuals with PDC.
MAM Rat Model: A Tool for Exploring the Role of Genomic Dysregulation in Neurodevelopmental Disorders.
Animal models are critically important for understanding the underling pathophysiology of psychiatric disorders. Currently, there are three general animal models of schizophrenia, (i) pharmacological intervention (ii) genetic and (iii) developmental disruption (e.g., MAM). There is compelling evidence that in utero administration of MAM to rats produces a valid animal model of schizophrenia (see Schizophrenia Research Forum, Developmental Preparations, http://www.schizophreniaforum.org/res/models/default.asp). Administration of MAM to rats during prenatal brain development produces an animal model of schizophrenia, yet the underlying mechanism is poorly understood. The abnormal development and migration of neurons are features commonly observed in the MAM rat model and the schizophrenic brain. The MAM GD17 rat model recapitulates a pathodevelopmental process leading to schizophrenia-like neuroanatomical and behavioral phenotypes. Along with Dr. Jacob Raber (Dept. of Behavioral Neuroscience, OHSU), we propose to determine if the neurochemical, neurodevelopmental and neurobehavioral features of schizophrenia in the MAM rat model are due to the ability of this model environmental genotoxicant to alter genomic stability (i.e., DNA damage) in the fetal brain. Studies are proposed to reduce the DNA repair capacity of the fetal rat brain (like that reported in the fetal human brain) using an established pharmacological approach (i.e., O6-benzylguanine) to determine which features of the pathodevelopmental process in the rat model are linked with MAM-induced DNA damage. If a significant proportion of these features are associated with DNA damage, future studies will be conducted in DNA repair mutant mice (i.e., Mgmt KO) to determine if specific DNA lesions (i.e., O6-mG) are triggering the effects.
MAM Influences Tau Pathology and Brain Development by an Epigenetic Mechanism
Dr. Birnbaum recently pointed out at a NAS workshop, “Animal studies indicate that some environmental chemicals cause epigenetic changes that trigger breast and prostate cancer, obesity, diabetes, heart disease, asthma, Alzheimer’s, Parkinson’s disease and learning disabilities, and some new human studies are now adding to the evidence.” Thus, epigenetic dysregulation is a common theme in neurological disorders. There is a growing body of evidence indicating that epigenetic mechanisms (i.e., histone modifications, chromatin remodeling enzymes, DNA methylation) that regulate normal brain development and function are perturbed in patients with neurodegenerative disease (e.g., AD) or psychotic disorders. Taken together, these studies suggest that environmental chemicals play a significant role in neurodegenerative disease or neurodevelopmental disorders by perturbing the epigenome during critical periods of brain development. In support of this hypothesis, recent gene expression profiles of the immature brain of Mgmt KO mice showed that MAM had a pronounced effect on chromatin remodeling genes and it produced significant changes in both the methylation and acetylation of histone (i.e., H3) proteins, but not DNA methylation. Since DNA lesions reportedly induce gene silencing by altering modified histone proteins (Khobta et al., Nucl Acids Res 2010 Mar 24), these provocative findings suggest that the DNA lesions produced by MAM in the developing brain alter chromatin structure leading to significant changes in the expression of genes that regulate tau or cell-signaling processes that are required to achieve brain maturation. Studies are proposed to determine if histone methylation and acetylation and the enzymes that modify histone proteins are altered by MAM in the brain of htau mice or the rat model of schizophrenia. Once the specific histone protein changes have been identified in each animal model, we propose to use a combination of chromatin immunoprecipitation (ChIP) and microarrays (i.e., ChIP on chip) to identify the genes that are specifically silenced or activated by MAM. These latter studies are expected to pinpoint the molecular networks that are specifically perturbed by the MAM-induced epigenetic changes in the underdeveloped brain. If our hypothesis is correct, these findings could explain how early life exposure to cycads leads to the tauopathy and cognitive decline in ALS/PDC patients as well as provide important insight into how this genotoxicant induces pathophysiological and neurobehavioral changes like those reported in schizophrenia.
“Professors known as outstanding lecturers do two things; they use a simple plan and many examples.” W. McKeachie. I have learned over the years, both through various teaching experiences and my interaction with colleagues, that the most effective way to motivate students to learn is to have a good balance of three things: clearly defined objectives, a challenging set of goals and large doses of encouragement.
One of the most enjoyable aspects of my training to be a scientist was teaching - sharing the knowledge and wisdom that I had accumulated and exchanging ideas with others. Many of my fondest memories of graduate school are the experiences I had teaching pharmacy students at the University of Texas at Austin (UT) and chemistry students at Austin Community College (ACC). As a teaching assistant in the Department of Medicinal Chemistry at UT, I was responsible for grading tests, presenting lab talks, and leading tutorial discussions for first- and second-year pharmacy students. My interaction with pharmacy students outside of the classroom (e.g., pharmacy student talent show, student sponsored events) was especially rewarding because it helped me get to know each student personally and made me a more effective TA. My passion for teaching at UT was one of the reasons I sought out additional teaching jobs in the Austin area. As a Chemistry Lecturer and Lab Instructor at Austin Community College (ACC), I was responsible for teaching an Introductory Chemistry Course and lab to freshman and sophomores. Unlike the students at UT, most ACC students were adults and many came from wider socioeconomic and educational backgrounds. I quickly learned to incorporate more interactive demonstrations within the classroom to get a particular point or theory across to the students. This experience taught me to be more creative in my teaching style. As a graduate student, I supervised a number of undergraduates (Pharmacy and non-Pharmacy majors) through the UT work-study program who assisted me with my cell culture experiments. I have taught in three graduate level courses as an Assistant or Associate Professor at OHSU and OSU: Topics in Neurotoxicology, Cell and Molecular Neurobiology, Neuroscience of Aging and supervised many theses and other research projects of students with diverse educational backgrounds (i.e., high-school to post-doctoral fellows). My experiences with high school students added a new set of challenges by requiring me to simplify advanced material for students with very limited background knowledge. My previous interactions with students of diverse educational background has taught me to recognize the differences in effectively designing introductory and advanced material, and I have learned to tailor my expectations based upon their knowledge base. Through these experiences, I have gained an appreciation of the complexities of teaching: how to select the appropriate instructional material for a particular course (or student), and most importantly, how to engage students who have varied educational, sociological, and cultural backgrounds. With this experience, I am confident I can teach any familiar subject in a fashion that would both engage and stimulate students.
I see the instructor, students, and course material all playing pivotal roles in the success of any class. As I continue to develop as a scholar and a scientist, and as the technology, treatment modalities, and students I teach change over time, my approaches to teaching and learning will undoubtedly adjust. Yet, what will remain is my objective in every instance: Use a simple plan and many examples.
DNA damage, DNA repair, neurodegenerative disease (Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis), and neurodevelopmental disorders (e.g., schizophrenia).
National Association for Schizophrenia 7/1/08 – 6/31/10
Research (NASARD), Young Investigator Grant
(Rob Merker, Columbia Univ, PI, Kisby, Consultant)
Genomic Instability in an Animal Model of Schizophrenia
The central goal of this project was to determine if MAM perturbs specific molecular and cellular networks in the brain of embryonic (E17) rats and whether these changes occur through a DNA damage-mediated mechanism. These findings provided unique insight into the distinct molecular mechanisms perturbed by an environmental agent and the developmental pathways that are relevant to the study of schizophrenia.
PI, Kisby 10/1/08 – 12/31/09
Oregon Partnership for Alzheimer's Total costs $25,000
Role of Environmental and Genetic Factors in Dementia
The major goal of these studies was to determine if early life exposure to the cycad genotoxin methylazoxymethanol (MAM) and inherent tau dysregulation are two important factors that contributed to the tau pathology in the prototypical neurodegenerative disorder western Pacific ALS/PDC. The effect of MAM on tau pathology was examined in the brain of mice that overexpress normal human tau (i.e., htau).
NIH/NIEHS (STAR Project, ES11384) 09/01/03 – 7/31/08
(Spencer, PI, Kisby Co-PI) Annual Direct Costs $149,679
DNA Alkylation in Neurodegenerative Disease and Cancer
The primary objective of this project was to determine if MAM induces persistent changes in the expression of genes that are linked with the etiopathogenesis of neurodegenerative disease and cancer. This hypothesis was examined by comparing the gene expression profiles of the adult brain and liver of wild type and DNA repair knock-out mice after treatment with MAM and related environmental genotoxins.
NIH/NIEHS (1P42 ES10338) 09/01/01 – 7/31/08
(Spencer, PI, Nagalla/Kisby Project 2 leaders) Annual Direct Costs $108,703
Role of Gene Expression in Brain Injury
The primary objective of Project 2 was to determine if the environmental genotoxin MAM induces persistent changes in the expression of genes that are linked with the etiopathogenesis of progressive neurodegenerative disease. This hypothesis was examined by comparing the influence of MAM on the gene expression profiles of neuronal and glial cell cultures and the developing brain of wild type and DNA repair mutant mice. Findings from these studies increased our understanding of the long-term impact of environmental agents on the developing nervous system and they provided insight into the their potential role in the etiopathogenesis of progressive neurodegenerative disease.
3/14/08 Patent applied for: High-Throughput Microtiter Plate Assays for DNA Damage and DNA Repair.
3/14/08 Patent applied for: Molecular-Scale Imaging and Quantification of DNA Damage in Single Cells using Nanoparticle Probes.
Society for Neuroscience
Society of Toxicology
Rho Chi Society (Academic Honor Society in Pharmacy)
American Chemical Society
New York Academy of Sciences
CROET Laboratory Manager (1988-1990)
CROET Faculty Search Committee (1993)
CROET Faculty Search Committee (1999)
CROET Research Committee (1999-2000)
CROET: Coordinator of Seminar Series (2003-2009)
OHSU: Awards/Prizes Committee (2003-2009) [Reviewed applications from junior investigators at OHSU for limited grant submissions (e.g., Searle, Keck, Pew Scholar awards… etc.)]
OHSU: Oregon National Primate Research Center (ONPRC) Promotions Committee: Ad-hoc reviewer (2009)
Kisby G.E., Spencer, P.S. Is neurodegenerative disease a long-latency response to early-life genotoxin exposure? Int. J. Environ. Res. Public Health, Special Issue: Environmental Neurotoxicology, (accepted 9-8-2011).
Kisby, G.E. Spencer, P.S. Comment on Nature Paper: Deng HX et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011 Aug 212011 Aug 21. doi: 10.1038/nature10353. [Epub ahead of print].
Kisby, G.E., Palmer, V., Lasarev, M.*, Fry, R.C.*, Iordanov, M., Magun, E., Samson, L.D., Spencer, P.S. Does the cycad genotoxin MAM implicated in Guam ALS-PDC induce disease-relevant latent changes in mouse brain that includes olfaction? Communicative and Integrative Biology, In press (Addendum to PloS One paper).
La Maestra, S.*, Kisby, G.E.*, Micale, R.T., Johnson J., Kow, Y.W., Bao G., F., Sheppard C., Stanfield S., Tran H., Woltjer R.L., D’Agostini F., Steele V.E., De Flora S. Cigarette smoke induces DNA damage and alters base-excision repair and tau levels in the brain of neonatal mice. Toxicological Sciences Jul 21, 2011 (* equal contribution).
Kisby, G.E.*, Lasarev, M.*, Fry, R.C.*, Bammler T., Beyer R., Cranson, A., Meira, L.B., Palmer, V., Ren, X., Sullivan R.C., Churchwell, M., Doerge, D., Crawford, A.L., Kavanagh, T., Samson, L.D., Zarbl, H., Spencer, P.S. The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner. PLoS One 6(6):e20911, 2011 (* equal contribution).
Spencer, PS, Palmer V, Lasarev, M, Kisby G.E. Neurotoxic cycad components and Western Pacific ALS/PDC. Ann Neurology 68:975-6, 2010 (Letter).
Muniz, J., McCauley, L., Pak, V., Lasarev, M., Kisby, G.E., Effect of sample collection and storage conditions on DNA damage in buccal cells from agricultural workers. Mutation Research - Genetic Toxicology and Environmental Mutagenesis 720:8-13.
Kisby, G.E., Olivas, A., Kohama, S.G., Doerge, D., Spangler, E., DeCabo, R., Ingram, D.K., Imhof, B., Koshy, M., Kow, Y.W. Effect of caloric restriction on base excision repair (BER) in the aging rat brain. Experimental Gerontology 45(3):208-16, 2010.
Kisby, G.E., Muniz, L., Scherer, J., Lasarev, Koshy, M., Kow, Y.W., McCauley, L. Oxidative stress and DNA damage in agricultural workers. Journal of Agromedicine 14:206-214, 2009 [Special Issue on PHARE International Symposium].
Kisby, G.E., Olivas A., Park T., Churchwell M., Doerge, D., Samson L., Gerson S.L., Turker M.S. DNA repair modulates the vulnerability of the developing brain to alkylating agents. DNA Repair 8:400-412, 2009.
Spencer, PS, Palmer V, Kisby G.E. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology 72:474-6, 2009 (Letter).
McCauley, L, Lasarev, M., Muniz, L., Anger, K, Kisby, G.E. Analysis of pesticide exposure and DNA damage in immigrant farmworkers. Journal of Agromedicine 13:237-246, 2008.
Muniz, J., Lasarev, M., Koshy, M., Kow, Y.W., Li, X., McCauley, L., Kisby, G.E. Biomarkers of oxidative stress are elevated among agricultural workers. Toxicology and Applied Pharmacology 15:227:97-107, 2008.
Kisby, G.E., Standley, M., Park, T., Olivas, A., Fei, S., Jacob, T., Reddy, A., Lu, X., Pattee, P., Nagalla, S.R. Proteomic analysis of the genotoxicant methylazoxymethanol (MAM) induced changes in the developing cerebellum. Journal of Proteome Research 5:2656-2665, 2006.