UMDNJ Magazine - fall 2004 VOLUME 1 NUMBER 1

Nancy D. Chiaravalloti, PhD, an assistant professor in the Department of Physical Medicine and Rehabilitation at UMDNJ-New Jersey Medical School, has received two grants to study cognitive functioning in individuals with multiple sclerosis (MS). The first grant for $1,370,000 is funded for five years by the NIH/National Institute of Child Health and Human Development.

Through a small randomized clinical study called "Treating New Learning in Multiple Sclerosis (MS)," Chiaravalloti demonstrated that individuals with MS who have documented memory impairment show a significant improvement in their memory performance following a treatment protocol utilizing imagery and context to facilitate learning.

Impairment in new learning and memory is one of the most common deficits in individuals with MS, impacting many aspects of everyday life, including employment status and social functioning. Chiaravalloti aims to replicate the earlier finding and further evaluate the impact of the treatment protocol on everyday functioning; observe the long-term effects of the treatment six months following its completion; and examine the usefulness of once-amonth "booster" sessions to maintain the treatment effects for more than six months.

The second grant for $428,000, funded by the National Multiple Sclerosis Society for three years, is for "Working Memory in MS: Using fMRI to Identify the Deficit." Many MS patients report difficulties with attention, concentration and memory. Research has shown that these deficits in their "working memory" may in fact be the source of some of these cognitive difficulties. The term working memory refers to the ability to hold and manipulate information in the mind (adding numbers without writing them down).

Chiaravalloti and her team are examining working memory abilities in 60 participants: 20 with MS who have an impairment in working memory functions, 20 with MS who do not have this impairment, and 20 healthy controls.

Human Exposure Modeling

Paul J. Lioy, PhD, (right) a professor and director of the Exposure Measurement and Assessment Division (EMAD) in the Department of Environmental and Occupational Medicine at UMDNJ-Robert Wood Johnson Medical School (RWJMS), and deputy director for government relations at the Environmental and Occupational Health Sciences Institute (EOHSI), and Panos A. Georgopoulos, PhD, (left) a professor in the division and director of the Computational Chemodynamics Laboratory at EOHSI, have been awarded a five-year, $2,499,903 renewal grant from the U.S. Environmental Protection Agency (EPA) for "Human Exposure Modeling - An Integrated Probabilistic Modeling Environment for Reducing Uncertainty in Human Health Risk Assessment: Characterizing Multipathway Human Exposure and Source-to-Dose Relationships."

The work completed by this team over the past five years led to the development of a modeling system for evaluating simple and complex environmental health problems. "Our approach follows the release of toxicants from sources and eventually helps us to estimate the dose received by a person or many persons," says Lioy.

Their Modeling Environment for Total Risk Studies (MENTOR) integrates concepts from environmental science, engineering, medicine, toxicology and epidemiology. The model improves human exposure and dose assessments used in evaluating risk. It helps to determine the interventions needed to characterize, reduce and eliminate local and national environmental health problems.

"The system's strength is its ability to incorporate new information within a very flexible modeling environment rather than build a new model every time one is needed to address an acute or chronic environmental health issue," says Georgopoulos.

Space Flight and the Immune System

Yufang Shi, DVM, PhD, University Professor in the Department of Molecular Genetics, Microbiology and Immunology at UMDNJRobert Wood Johnson Medical School, has been awarded a $1,747,312 grant from the National Space Biomedical Research Institute,which is supported by NASA, for "Apoptosis and Immune Homeostasis During Hind Limb Unloading." This new project is a continuation of his current study, "Effects of Antiorthostatic Suspension on the Immune System."

Evidence indicates that astronauts have significantly increased rates of infection after their flights. Shi is simulating space flight conditions to study the effect on the immune system in an animal model. He has demonstrated that lymphocyte numbers are dramatically reduced and the immune response is significantly altered under these conditions.

"We propose to further investigate the cellular and molecular mechanisms affecting the immune system during space flights," says Shi. "Our goal is to elucidate the role of Fas and endogenous opioids in the modulation of the immune system by hind limb unloading and determine the effect of hind limb unloading on lymphocyte dynamics and immune responses."

Indentifying Neutral Circuitry for Rage & Agression

Allan Siegel, PhD (bottom), professor of neurology and neurosciences and psychiatry, and Steven S. Zalcman, PhD, assistant professor of psychiatry, both at UMDNJ-New Jersey Medical School, have been awarded a five-year, $1,637,188 grant from the NIH/National Institute on Neurological Disorders and Stroke to identify the neural circuitry and neurochemical and neurophysiological mechanisms that underlie the expression and control of rage and aggressive behavior. The primary focus of this study, which represents a major new direction in their research program, is to recognize and characterize the roles of serotonin and cytokines in the medial hypothalamus in regulating these forms of aggression.

This rationale is based upon our most recent preliminary studies," says Siegel. "We provide evidence that, in the medial hypothalamus, 5-HT1A and 5-HT2 receptors and cytokines IL-1R and IL-2 powerfully modulate defensive rage behavior in our animal model. The overarching hypothesis is that differential cytokine effects upon defensive rage and predatory attack are mediated principally through distinct neurotransmitter receptors of which serotonin and possibly GABA are primary candidates."

Five experiments are proposed to test this hypothesis. The first will utilize immunocytochemical and neuroanatomical methods to characterize the pathway from midbrain periaqueductal gray (PAG) to the medial hypothalamus mediating defensive rage and its relationship to serotonin axons and pre-terminals in this region. The second will determine the effects of 5-HT1A and 5-HT2 receptors in the medial hypothalamus on defensive rage. The third will determine the role of IL-1R in the medial hypothalamus on defensive rage, its relationship to 5-HT2 receptors, the distribution of IL-1R in this region and its relationship to serotonin axons and pre-terminals as well as to c-Fos labeled neurons following the expression of defensive rage. The fourth experiment will seek to determine the role of IL-2 in the medial hypothalamus on defensive rage and the underlying neurotransmitterreceptor mechanism. The fifth will identify the effects of activation of 5-HT and the above cytokines on predatory attack behavior.

"The discovery that cytokines in the brain play a significant role in defensive rage represents a most significant observation," says Zalcman. "It has provided an entirely new direction of research with a focus that will address how cytokines and related substances in the brain may play critical roles in the expression and control of aggression and rage."

Network Connections in the Nervous System Development

William G. Wadsworth, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at UMDNJRobert Wood Johnson Medical School, has been awarded a five-year, $1,772,300 grant from the NIH/National Institute of Neurological Disorders and Stroke to study "Extracellular Matrix and Axonal Guidance in C. elegans."

Our laboratory is studying the molecular mechanism by which nerve cells form intricate networks of connections during nervous system development," explains Wadsworth. "Many of these mechanisms are consistent among all animals and in our studies we use a model organism called C. elegans.We are able to make genetic mutants and observe nervous system development in this transparent nematode."

Much of the work has focused on a molecule named UNC-6, which Wadsworth co-discovered as a postdoctoral fellow at The John Hopkins University. UNC-6 is the founding member of the netrin family of proteins. The netrins help guide the nerve cells to make correct connections in vertebrate animals, including humans. Understanding the mechanisms of nervous system development could aid in developing therapeutic agents to treat nerves damaged by injuries or disease.

Investigation the Fuctional Properties of Proteins

Andrew L. Harris, PhD, an associate professor in the Department of Pharmacology and Physiology at UMDNJ-New Jersey Medical School, has received a four-year, $1,169,990 grant from the National Institutes of Health to study channel-forming proteins. His lab investigates the functional properties of proteins that form gap junction channels, which are intercellular pores through which ions and small molecules pass from cell to cell. In neurons they form electrical synapses. These pores mediate intercellular electrical and molecular signaling, important in neurobiology, physiology, development and disease.

Gap junction channels are oligomers of connexin (Cx) protein, of which there are at least 20 isoforms," he says, explaining that channels formed by each isoform seem to have distinct intercellular signaling functions. "Defects in a single isoform cause a distinctive phenotype, such as neuronal demyelination (Cx32), deafness (Cx26), cardiac malformation (Cx43), cataracts (Cx50) and susceptibility to cancer (Cx32). These connexin-defect phenotypes arise from disruption of normal molecular movement through connexin channels. Control of this molecular movement is the primary focus of our work." The lab uses physiological, biochemical and genetic approaches to explore channel structure/function. Connexin channels are studied at macroscopic and single-channel levels in reconstituted and expression systems. Genetically altered connexins are used to define permeation and modulation mechanisms. A particular focus is on the functional contributions of connexin domains and isoforms to channel function. Connexin channels are pathways for direct movement of cytoplasmic molecules between cells. In spite of considerable knowledge about connexin channels, the character and mechanism of their most salient property - selective permeability among signaling molecules - remains largely unknown.Which chemical signals pass through connexin channels and how selectivity among them is achieved, are fundamental issues with far-reaching impact.

"We seek to define these processes," he says. "The channels formed by each of the ~20 varieties of connexin differ from one another with regard to molecular permeability. The importance of this specificity is demonstrated by the fact that every functional deletion of a connexin type produces a distinct pathology, such as neuronal demyelination, deafness, cardiac defects, cataracts or infertility."

An Oral Bacterium That Affects Adolecents

Jeffrey B. Kaplan, PhD, an assistant professor in the Department of Oral Biology at UMDNJ-New Jersey Dental School, was awarded a fouryear, $857,151 grant from the NIH/National Institute of Dental and Craniofacial Research to study an oral bacterium that causes a form of periodontal disease affecting adolescents.

Many bacterial species are able to attach to surfaces and form biofilms, which cause dental caries, periodontal disease, infective endocarditis and other chronic infections. This bacterium, known as Actinobacillus actinomycetemcomitans, or Aa, forms tenacious biofilms in plastic dishes, and is capable of spreading across the surface of the dish.

"I was interested in studying this spreading phenomenon," says Kaplan, "and discovered that Aa cells secrete an enzyme that digests the slime layer and releases bacterial cells from the biofilm, which enables it to spread."

Kaplan and his team used genetic engineering to purify large amounts of this enzyme and found that it causes the detachment of preformed Aa biofilms from surfaces.

"The most exciting finding was that this enzyme causes the detachment of biofilms produced by a wide variety of bacterial species, suggesting that it may be useful as a broad-spectrum anti-biofilm agent," he explains.

Gene Mapping to Periodontitis

Scott R. Diehl, PhD, director of the Center for Pharmacogenomics and Complex Disease Research at UMDNJ-New Jersey Dental School, has been awarded a five-year, $1,846,563 grant from the NIH/National Institute of Dental and Craniofacial Research to study "Gene Mapping of Susceptibility to Periodontitis."

Genetic differences among individuals have major effects on the risk of chronic periodontitis, the focus of this new study. This disease affects more than 20 % of adults age 40 and is the major cause of tooth loss in older Americans. Periodontitis may also increase risk of cardiovascular disease, osteoporosis, and in women of childbearing age,may be associated with preterm delivery and low birth weight. Chronic periodontitis is a "complex disease." Both inherited genetic variation and environmental factors, such as smoking, hygiene and pathogenic bacteria, determine individuals' risk. Diehl's previous studies of adult twins demonstrated that the disease has a heritability of 50 percent, indicating that genes and environment play about an equal role in determining whether a person is affected. Diehl's Center incorporates advanced molecular genomics and bioinformatics techniques for analyses of single nucleotide polymorphisms (SNPs) and statistical genetic strategies such as haplotype mapping that greatly increase power to identify genes' underlying complex traits. A critical component needed for success in this approach is availability of very large, high-quality clinical populations. Diehl and his team will test more than 100 candidate genes for association with periodontitis in 8,000 subjects recruited in the U.S. Discovery of specific gene mutations may lead to improved therapies designed to correct biochemical aberrations caused by the gene defects. Different therapeutic approaches may be targeted to address different gene defects rather than a "one size fits all" approach used today. "It is important to recognize that absence of a simple one-to-one mapping between disease gene and clinical phenotype in a complex disease such as periodontitis doesn't necessarily diminish the value of identifying genes that determine individual differences in susceptibility," says Diehl. "These genetic variants still have great potential to explain a substantial portion of disease risk in the population and to predict risk for individuals."

New Jersey Dental School Publications:

"Comparison of Direct and Conventional Intraoral Radiographs in Detecting Alveolar Bone Loss" by Ahmed Khocht, DDS, MSD, clinical associate professor, Malvin Janal, PhD, senior research associate, Lynn Harasty, DMD, clinical associate professor, and Kuang-min Chang, DMD, PhD, associate professor, all in Periodontics, was in JADA, Vol. 134, November 2003.

"Sensory Responses from Loading of Implants: A Pilot Study" by Barry Simon, DDS, MSD, professor, Periodontics, Harry Zohn, DMD, clinical associate professor, Periodontics, Neal Lehrman, DMD, clinical associate professor, Periodontics, Saul Weiner, DDS, professor, Restorative Dentistry, and David Ehrenberg, DDS, MS, assistant professor, Restorative Dentistry, et. al., was in the International Journal of Oral and Maxillofacial Implants,Vol. 19, No. 1, 2004.

Professional Activities:

Maano Milles, DDS, professor, Oral & Maxillofacial Surgery, presented “Alternative Methods of Mandibular Reconstruction” at the Northern Regional Hospital at Mustame, Tallinn, Estonia.

New Jersey Medical School Grants:

Maha Abdellatif, PhD, assistant professor, Cell Biology and Molecular Medicine, received a four-year, $800,000 grant from the NIH/National Heart, Lung and Blood Institute for “Mechanisms of RasGAP in Cardiac Cell Growth and Survival.”

Mark S. Johnson, MD, MPH, professor and chair, Family Medicine, Debbie Salas-Lopez, MD, assistant professor, Clinical Medicine, and Paulette Stanford, MD, associate professor, Pediatrics, received a three-year, $988,000 grant from the Department of Health & Human Services, Health Resources and Services Administration to establish a Primary Care
Research Consortium.

Neerja Kaushik-Basu, PhD, assistant professor, Biochemistry and Molecular Biology, received a four-year, $800,000 grant from the NIH/National Institute of Diabetes, Digestive and Kidney Disorders for “Molecular Modulators of HCV Replications.”

Yoshihiro Ishikawa, PhD, professor, Cell Biology and Molecular Medicine, received a four-year, $840,000 grant from the NIH/National Institute of
General and Medical Sciences for “Catalytic Activation of Adenylyl Cyclase Type V.”

Karen Quigley, MD, assistant professor, Neurology and Neurosciences, received a threeyear, $760,940 grant from the Department of Veterans Affairs for “Risk Perception and the Psychobiological Sequelae of Vaccination.”

Ian Whitehead, PhD, assistant professor, received a four-year, $800,000 grant from the American Cancer Society to study "RhoGEFs in Cell Growth and Cancer." These studies will examine the role of small GTPases in malignant progression with emphasis on breast cancer.

Publications:

"Critical Review of Prolotherapy for Osteoarthritis, Low Back Pain, and other Musculoskeletal Conditions: A Physiatric Perspective," by Sunny Kim, MD, resident, Todd Stitik, MD, associate professor, Patrick Foye, MD, assistant professor, and Denise Campagnolo, MD, associate professor, Physical Medicine and Rehabilitation, was in the American Journal of Physical Medicine and Rehabilitation, Vol. 83, No. 5.

“The Economic Burden of Hospitalizations Associated with Child Abuse and Neglect,” by Sue Rovi, PhD, assistant professor, Ping-Hsin Chen, PhD, assistant professor, and Mark Johnson, MD MPH, was in the American Journal of Public Health, Vol. 94, No. 4, 2004.

Robert Wood Johnson Medical Scool Publications:

“Epigenetic Dynamics of Imprinted X Inactivation During Early Mouse Development,” an online article, co-authored by Danny Reinberg, PhD,
Distinguished University Professor of Biochemistry and Investigator, Howard Hughes Medical Institute, was in Science, December 2003.

“Structured Treatment Interruption in Patients with Multidrug-Resistant Human Immunodeficiency Virus,” by last author and protocol co-chair, John D. Baxter, MD, associate professor of medicine, was in The New England Journal of Medicine, Vol. 349, No. 9, 2003.

Grants:

Benjamin Crabtree, PhD, professor, Family Medicine, received a three-year, $600,000 grant from the Robert Wood Johnson Foundation for "Prescription for Health: Promoting Healthy Behaviors in Primary Care Research Networks."

Ramsey Foty, PhD, assistant professor, Surgery, received a three-year, $575,127 grant from the U.S. Army to study "Quantifying Tumor Endothelial Cell Interaction in Organotropic Prostate Cancer."

Michael Gallo, PhD, professor, Environmental and Occupational Medicine, received a one-year, $731,000 grant from the U.S. Environmental Protection Agency to study "Influence of Environmental Factors in Cancer Causation."

Peter Lobel, PhD, professor, Pharmacology, and resident member, CABM, received a one-year, $342,354 grant from the NIH-National Center for Research Resources for the purchase of a Nanospray Liquid Chromatography Tandem Mass Spectrometry System.

James Millonig, PhD, assistant professor, Neuroscience and Cell Biology, received a two-year, $399,967 grant from the New Jersey Commission on Spinal Cord Research for “The Development of Spinal Cord Therapies Through a Genetic Analysis of Mouse Spinal Cord Development.”

Gaetano Montelione, PhD, adjunct professor, Biochemistry, received a one-year, $760,000 grant from the National Institute of General Medical Sciences for “Acquisition of 800 MHZ NMR System with Cryogenic Probe.”

Cory Abate-Shen, PhD, resident member, CABM, leader, Prostate Program, CINJ, professor, Medicine and Neurosciences and Cell Biology, and chief, Division of Developmental Medicine and Research, received a five-year, $4,485,615 consortium grant for "A Mouse Model for Prostate Cancer".

The Institute for the Study of Child Development received its first fMRI
grant, $465,000 for three years, to study “The Relationship Between
Brain Functioning and Performance.” In collaboration with the RWJMS Department of Radiology, it will study how differences in adolescents’ inhibitory behavior is related to brain activity as a function of prenatal cocaine exposure.

Jin-Ming Yang, PhD, associate professor, Pharmacology, received
a two-year, $384,863 grant from The National Cancer Institute to
“Study the Role of Ubiquitinin in Cancer Progression.”

James Zheng, PhD, associate professor, Neuroscience and Cell Biology, received a two-year, $364,092 grant from the New Jersey Commission on Spinal Cord Research to study “Inhibitory Mechanisms of Axonal Growth in Spinal Neurons.”