Research News & Grants
compiled and edited by Carole Walker & Doris Cortes-Delgado
Understanding the Role of a DNA Repair Protein
Madura’s lab has been studying Rad23, a multi-functional protein that recognizes and binds damaged DNA during nucleotide excision repair. DNA is frequently damaged by many environmental agents. Nucleotide excision repair (NER) is an important mechanism for removing a wide spectrum of different DNA lesions. Defects in the repair pathway are associated with cancer, neurodegeneration, and various cognitive and developmental
“Our primary goals are to investigate the role of Rad23 in protein degradation and to define the significance of this activity in repairing DNA damage,” says Madura.
His team is also studying the role of Rad23 in controlling the stability of the DNA repair protein Rad4. Mutations in the human homolog of Rad4 lead to xeroderma pigmentosum, a debilitating disease in which individuals are extremely sensitive to sunlight. Studies of Rad23 have led to an interest in understanding the consequence of deficient protein degradation in human neurodegenerative diseases. Madura’s team described the first biochemical function for the ataxin-3 protein. Ataxin-3 interacts with Rad23. Mutations in the protein cause Machado-Joseph disease, also known as spinocerebellar ataxia-3, a rare hereditary disorder affecting muscle control. In other studies, the group is characterizing the proteins alpha-synuclein and Parkin, which are causative factors in Parkinson’s disease.
Sodium-Calcium Exchange and the Heart
The sodium-calcium exchanger is located in the plasma membrane of cardiac myocytes, as well as in many other excitable cells, and couples the movement of calcium ions across the membrane to the movement of sodium ions in the opposite direction. It normally pumps calcium ions out of the cell, but when there is an increase in the cytosolic sodium concentration and/or a depolarization of the cell membrane, the exchanger can run backwards and bring
calcium into the cell.
In the heart, the exchanger is one of the many regulatory processes that control the strength of cardiac contraction by modifying the cellular calcium content. It is an important component of the mechanism by which digitalis increases the strength of cardiac contraction in patients with congestive heart failure. Exchange activity can also be deleterious to cardiac function, however. Following cardiac ischemia, for example, the increased concentrations of cytosolic sodium and calcium can induce life-threatening cardiac arrhythmias due to the currents generated by excessive sodium-calcium exchange activity.
“Our lab is investigating the mechanisms that regulate exchange activity,” says Reeves. “This occurs through regulatory effects induced by cytosolic sodium and calcium ions, and by interactions between the exchanger protein and the cytoskeleton.” Many investigators feel that this regulatory effect of calcium ions turns the exchanger “on” during cardiac muscle contraction, when cytosolic calcium concentrations are high, and turns the exchanger “off” during cardiac muscle relaxation, when cytosolic calcium concentrations are low. His team’s results, however, reveal that exchange activity does not turn off immediately when calcium concentrations decline, implying that its activity persists even during muscle relaxation.
Burn Injury and Cardiac Dysfunction
Burn injury has been shown to initiate a series of pathophysiological changes. A progressive fall in left ventricular (LV) contractile function, despite aggressive fluid resuscitation, has been reported in both clinical and experimental studies of burn injury. But the mediators of the cellular signaling mechanisms that determine the burn-induced myocardial dysfunction are not well understood.
Recent studies by Deitch indicate that gut-derived myocardial depressant factors carried in intestinal lymph trigger myocardial contractile depression. This is based on the observation that ligations of the main mesenteric lymph duct prior to burn injury significantly prevented burn injury-induced left ventricular contractile dysfunction, as measured in ex vivo isolated heart experiments.
However, there are no systematic studies that have examined the effects of burn injury on myocyte function, so the cellular and molecular mechanisms responsible for burn-induced left ventricular dysfunction are not clearly defined. The salutary effects of lymph duct ligation cannot be identified in the absence of this fundamental information.
“I believe this research has great potential for developing novel ways to prevent burn-induced ventricular dysfunction, using molecular therapies that limit a predisposing factor for developing aberrant Ca2+ flux to maintain normal cell function,” explains Yatani.
New Tissue Microarray System
Tissue microarray (TMA) technology is a relatively new approach for efficiently and economically assessing protein and gene expression across large ensembles of tissue specimens. TMA technique maximizes limited tissue resources and provides an effective means for visualizing molecular targets. Using TMAs, a carefully planned array can be constructed with cases from pathology tissue block archives, such that a survival analysis can be performed on a cohort of hundreds of patients using only a few micro-liters of antibody.
Currently, the primary methods for evaluating the arrays involve manual, interactive review of TMA samples while they are subjectively evaluated and scored. An alternate involves sequentially digitizing each specimen for subsequent semi-quantitative assessment. Both procedures involve the interactive evaluation of TMA samples, which is a slow, subjective process that is prone to error.
The team’s primary objective is to design, develop and evaluate a
web-based system for performing unsupervised-imaging, analysis and archiving of cancer tissue microarrays. The system utilizes a combination of sophisticated image processing and pattern recognition strategies to systematically image and co-register specimens at multiple optical magnifications, extract spectral and spatial signatures of the tissue, and populate local and/or distributed databases with the resulting metadata and imaged arrays.
By coupling the TMA analysis algorithms with modern discovery tools, the system will enable investigators to automatically mine and share experimental results and specimens from decentralized sources.
Partnership in Environmental Public Health
The project is one of four, five-year awards for Academic Partners for Excellence
in Environmental Public Health Tracking (EPHT), funded by the Centers for Disease Control to assist state and city health departments in developing the infrastructure to collect environmentally relevant health outcome data, and to support these agencies in assessing whether or not the observed outcomes are associated with specific environmental hazards. This UMDNJ project has three objectives.
The first is to review the types of data collected in some of the health data monitoring systems run by state and city health departments throughout the U.S. to determine if collection of additional types of environmentally related data would increase the likelihood of detecting a problem if one exists.
“This will likely include birth certificates, cancer registries and death
certificates,” says Wartenberg.
The second objective is to develop and refine the statistical methodology used to identify associations between environmental hazards and disease occurrence.
Their final objective is to work with state and city health departments in the Northeast to conduct epidemiologic studies of environmental hazards and disease occurrence. The team may look at the burden and risk factors of asthma in children, risk factors for cancer in children, and the frequency of adverse birth outcomes associated with arsenic in drinking water and air pollution. n
Developmental Disabilities Services
The division’s interdisciplinary team utilizes a biopsychosocial approach for clearer identification of factors contributing to mental health problems in
persons with developmental disabilities. Clinical staff includes a clinical director, board certified psychiatrists, licensed clinical and behavioral
psychologists, and advanced practice nurses with prescriptive powers.
“All are dually trained in the diagnosis and treatment of psychiatric illness and behavior disorders in persons with developmental disabilities,” says Tracey. The staff also teaches medical students, trains psychiatrists, and supervises residents and nurses in the diagnosis and treatment of psychiatric illnesses and behavior disorders affecting individuals with developmental disabilities.
The team provides training to direct care staff, care givers and family members on implementation of medication regimens, behavioral interventions and therapeutic techniques that lessen the possibility of crisis and on how to support successful maintenance of these individuals in their homes, schools, day centers or in alternative living settings.
The Crisis Intervention Program serves individuals age18 and older. Clients have a developmental disability and may have a coexisting psychiatric and/or behavioral disorder, and may be at risk of acute or long-term psychiatric hospitalization and/or loss of their residential placements in the community. Services are available around the clock. The program’s goal is early intervention when these individuals are in crisis so they can be stabilized and remain in the community where treatment can be provided in
community outpatient centers.
Neerja Kaushik-Basu, PhD,
assistant professor, Biochemistry and Molecular Biology, received a two-year, $426,682 grant from the National Institutes of Health-NIAID for “Effectors and Inhibitors of SARS Polymerase.”
Reynard McDonald, MD,
professor, Medicine, received a one-year, $795,052 grant from the CDC, through the New Jersey Department of Health and Senior Services, to provide tuberculosis prevention
activities in the Essex-Union area and to serve as the statewide MDR-TB referral
Lester Sultatos, PhD, associate professor, Pharmacology and Physiology, received a three-year, $938,575 grant from the NIH for “Insecticide Interactions with Acetylcholinesterase.”
“Physicians with Disabilities: Why Aren’t There More of Them?” by Joel DeLisa, MD, chair, Physical Medicine and Rehabilitation, an editorial in the AAMC Reporter.
“Successful Intraoperative Use of Recombinant Tissue Plasminogen Activator During Liver Transplantation Complicated by Massive Intracardiac/Pulmonary Thrombosis” by
Douglas Jackson, MD, JD,
assistant professor and director, Cardiac Anesthesia, Andrei Botea, MD, assistant professor, Yurly Gubenko, MD, assistant professor, Ellise Delphin, MD, MPH, professor and chair, and Henry Bennett, PhD, director, Clinical Research, all in Anesthesiology, was in Anesthesia & Analgesia, Vol. 102, 2006.
“The Calcium with Vitamin D Trial” by Norman L. Lasser, MD, PhD, director, Women’s Health Initiative, was in The New England Journal of Medicine, February, 2006 and the “Low-Fat Diet Study” was in the Journal of the American Medical Association, February 2006.
“Transformation of Breast Cells by Truncated Neurokinin-1 Receptor is Secondary to Activation by Perprotachykinin-A Peptides” by Pranela Rameshwar, PhD, associate professor, Medicine, Division of Hematology/Oncology, was in the Proceedings of the National Academy of Sciences, Vol. 102, 2005.
Cory Abate-Shen, PhD, professor, Neuroscience and Cell Biology, and chief, Division of Developmental Medicine and Research, and co-director, Prostate Cancer Program, CINJ, received a three-year, $568,904 grant from the Department of the Army for “Chemoprevention of Prostate Cancer in Mutant Mice: Targeting the Androgen Receptor Signaling Pathway.”
Tulin Budak-Alphdogan, MD, assistant professor, Medicine, received a three-year, $678,717 grant from the Lymphoma Research Foundation for “Post Transplant High-Dose MTX-ARA-C Consolidation: A Drug Resistance Gene Transfer Strategy for Myeloprotection.”
Kiran Chada, PhD, professor, Biochemistry, received a three-year, $444,472 grant from the Department of the Army for a study on “HMGA2 in Tuberous Sclerosis.”
Jeffrey Carson, MD, professor, Medicine, received a three-year, $2,265,210 grant from the National Heart, Lung and Blood Institute. The FOCUS grant is a multi-center randomized trial to test a more aggressive blood transfusion strategy in surgeries to repair hip fractures.
Huizhou Fan, MD, PhD, assistant professor, Physiology and Biophysics, received a two-year, $413,750 grant from the National Institutes of Health for “Specific Inhibition of Chlamydia with Hydroxamates.”
William Hait, MD, PhD, professor, Medicine, and director, CINJ, received a five-year, $1,250,000 grant from the National Cancer Institute to support The New Jersey Family Practice Research Network and the Protein Structure Analysis Core.
Henry Lisa, MD, clinical instructor, Surgery, received a five-year, $646,312 grant from the National Institute of General Medical Sciences for “Role of Wound Provisional Matrix in Endothelial Foundation.”
Leroy Liu, PhD, professor, Pharmacology, received a five-year, $1,527,309 from the National Cancer Institute for a grant in cancer pharmacology.
James Millonig, PhD, assistant professor, Neuroscience and Cell Biology, received a five-year, $2,261,512 grant from the National Institute of Mental Health for “Identification and Functional Assessment of Autism Susceptibility Genes.”
“Suppression of NF-kB-
mediated Beta-Defensin Gene Expression in the Mammalian Airway by the Bordetella Type III Secretion System” by Gill Diamond, PhD, associate professor, Oral Biology, was in Cell Microbiology, Vol. 7, 2005.
“The Actinobacillus Actinomycetemcomitans Autotransporter Adhesin Aae Exhibits Specificity for Buccal Epithelial Cells of Human and Old World Primates,” by Jeffrey Kaplan, PhD, assistant professor, Oral Biology, was in Infection and Immunity, Vol. 73, 2005.
Chinnaswamy Kasinathan, PhD, associate professor, Oral Biology, received a two-year, $1,943,700 grant from the National Institutes of Health for “Structure/Function Studies of Bio-Film Agents from Aa.”
“Nutrition Screening and Assessment in Older Adults” by Maureen Huhmann, MS, instructor, Primary Care, and Riva Touger-Decker, PhD, associate professor and program director, Applied Physiology, was in Today’s Dietitian, 2005.
“Weighing the Evidence: Energy Determinations Across the Spectrum of Kidney Disease” by Laura Byham-Gray, PhD, RD, was in the Journal of Renal Nutrition, Vol. 16, No. 1, 2006.
Laura Byham-Gray, PhD, RN, presented “Scope of Dietetics Practice: 21st Century Dietetics Practice - The Evolving Role of the Dietitian” at the National Kidney Foundation’s Annual Meeting in Washington, D.C.
“Attitudes Toward Advance Directives and Advance Directive Completion Rates” by Susan Salmond, EdD, RN, associate dean for Administration and Planning, was in the Orthopaedic Nursing Journal, Vol. 24, No. 2.
Sara Torres, PhD, RN, FAAN, dean, presented “Educational Mobility: Recruitment and Retention of Hispanics into Nursing” at the National Latino Education Summit in Las Vegas.
“Stillbirths in the United States, 1981-2000: An Age, Period and Cohort Analysis” by Cande Ananth, PhD, MPH, MS, associate professor, Epidemiology, and associate professor, Obstetrics, Gynecology and Reproductive Sciences, RWJMS, et al., was in the American Journal of Public Health, Vol. 95.