Division of Neurobiology
To contact the Division office, please call Adriana Fonseca at 443-287-4962.
The Division of Neurobiology has the ultimate goal of understanding the neurobiology of psychiatric diseases and translating that understanding into effective clinical treatments. It currently comprises basic science labs of six faculty members, as well as clinical research and services in Huntington's disease. The Division has close associations with clinical and genetic research programs n schizophrenia and with imaging research programs directed at a variety of diseases. We apply modern techniques of molecular biology and genetics to the study of normal brain functioning and neuropsychiatric disorders. We are committed to applying interdisciplinary approaches in order to understand and find effective treatments for diseases affecting the brain. Some of the diseases we study include Huntingtons disease, Parkinsons disease, bipolar disorder, and schizophrenia.
The laboratories in the Division use methods ranging from cellular and molecular to systems and behavior. Thus a problem in any disease area can be approached from a multidisciplinary standpoint with a wide range of expertise available. People in different labs are encouraged to collaborate and bring together their unique approaches to problems and to reach out to investigators in other programs and departments, both basic and clinical. Ultimately, the goal is to elucidate the basic biology of brain disorders and to develop biomarkers and novel therapeutic approaches that can be brought to human clinical trials.
- Genetic Neurobiology - Russell L. Margolis, M.D.
- Molecular Neurobiology - Christopher Ross, M.D., Ph.D.
- Translational Neurobiology - Wenzhen Duan, M.D., Ph.D.
Three core beliefs underlie research in the Division of Neurobiology.
- First, the most effective research is highly interdisciplinary. Division faculty labs use approaches ranging from basic biochemistry and biophysics, to cell biology and mouse genetics to preclinical and clinical therapeutic trials.
- Second, the powerful techniques of molecular and cell biology that are being used so successfully to unravel the basic biology of neurodegenerative diseases can now be applied productively to schizophrenia and other complex psychiatric diseases. Study of the rare familial forms of neuropsychiatric diseases is likely to illuminate the biology of the more common, apparently sporadic forms of these diseases.
- Finally, we believe in a translational orientation with the goal of developing biomarkers and experimental therapeutics that can be brought to clinical trials with patients.
The Huntington's Disease Model
The work in Huntington’s disease has provided a model to approach psychiatric diseases. Expansion of a CAG repeat in the huntingtin gene causes expansion of a polyglutamine stretch in the huntingtin protein, altering its structure, and causing cell toxicity and neuronal degeneration. We conducted some of the first studies to identify the abnormal huntingtin protein and to determine toxic mechanisms. We have also identified novel genes causing HD-like diseases. We created some of the first cell models of HD, and used them to screen for compounds which can block toxicity. We generated a transgenic mouse model of HD, which has helped to elucidate pathogenesis and is now one of the models used for preclinical therapeutic studies. Studies of the huntingtin protein contributed to the identification of the neuronal intranuclear inclusions which are the pathologic hallmark of the disease and which have begun to define an aggregation pathway. We contributed to the discovery that huntingtin interferes with gene transcription. This is now one of the major therapeutic strategies being tested in clinical trials of patients. Current studies focus on proteolytic modifications including proteolytic cleavage of huntingtin, aggregation gene transcription, and other cellular events leading to toxicity. Preclinical studies include testing therapeutics in cell and mouse models. We also study the disease closely related to HD termed HDL2. See the labs of Drs. Duan, Margolis, and Ross.
We have used similar techniques to approach Parkinson’s disease (PD). We studied the protein interaction partners of alpha-synuclein, the protein product of a gene mutated in familial PD. We identified an interaction between alpha-synuclein and protein we termed synphilin-1 and later showed that synphilin-1 interacts with another PD gene product termed parkin. We generated cell models expressing mutant alpha-synuclein and yielding cell death in culture. More recently, we have begun studies of the newly identified Parkinson’s disease gene termed LRRK2. We found that LRRK2 interacts with other PD-related gene products including synphilin-1 and parkin in cells in culture. We have also found that LRRK2 causes robust neuronal degeneration in cells and culture. Furthermore, we have found that kinase activity of LRRK2 is involved in cell toxicity, suggesting therapeutic targets. Current studies focus on mechanisms of alpha-synuclein aggregation and toxicity, cell and mouse models using LRRK2, and preclinical therapeutics. See the labs of Drs. Duan, and Ross.
Similar techniques are now being used to study schizophrenia. Unlike the degenerative diseases, schizophrenia is believed to be caused by abnormal neurodevelopment. The schizophrenia candidate gene DISC-1 is mutated in a familial form of schizophrenia. DISC-1 interacts with a number of proteins implicated in neuronal development and mutations of DISC1 interfere with neuronal differentiation and development both in vitro and in vivo. We are currently generating and studying cell and mouse models using mutant DISC-1 and other candidate genes and developing models based on gene-environment interactions. We are also searching for novel genetic causes of schizophrenia. See the labs of Drs. Margolis and Ross.
Faculty collaborate with research being done by the Division of Psychiatric Neuroimaging on a number of disorders, especially Huntington's disease.
We have a range of educational and training programs including a fellowship training program, contributions to residency training, and opportunities for graduate and post-graduate researchers. Techniques used in the basic science labs include molecular biology, cell biology, biochemistry, and cell and mouse models of disease. Clinical research on Huntington's disease, cerebellar and related disorders involves neuropsychiatric evaluation, neuropsychological testing, neuroimaging, and clinical trials of experimental therapeutics.
As one of the Division's training opportunities, this National Institute of Health-funded program permits individuals who have completed their residency or doctoral program to participate in either clinical or basic science training relating to neuropsychiatric diseases. Candidates for this program must be U.S. citizens or permanent residents. Applications from individuals who are members of under-represented minorities, have disabilities, or are from an economically disadvantaged background are strongly encouraged.
If you are interested in this or any aspect of our training program, please read about the work of the various laboratories to see the range of basic and clinical research being done in the Division as well as the clinical services being offered in the Baltimore Huntington's Disease Center and then contact Dr. Ross.
Dr. Christopher Ross is Professor of Psychiatry and Neuroscience at Johns Hopkins University School of Medicine. He received his M.D. and Ph.D. in Neuroscience at Cornell University School of Medicine and had clinical training in Psychiatry and Neuropsychiatry at Johns Hopkins. He then pursued post-doctoral work in the laboratories of Solomon Snyder at Johns Hopkins and Axel Ullrich at the Max Planck Institute in Martinsreid, Germany.
His lab focuses on the neurobiology and neurogenetics of neuropsychiatric disorders including Huntington's disease (HD), Parkinson's disease, schizophrenia, and others. He is Director of the Baltimore Huntington's Disease Center at Johns Hopkins, one of the two NIH-funded centers for the study of HD in the United States. The research in the different groups in the Center ranges from constructing cell and mouse models of HD to clinical and imaging studies of HD patients to clinical trials of novel therapeutic agents. He has sponsored trainees at the predoctoral, postdoctoral, and junior faculty levels, and his former trainees have faculty positions in the United States, Europe, and Japan.
- Professor, Departments of Psychiatry, Neurology, and Neuroscience
- Program in Cellular and Molecular Medicine
- Director, Laboratory of Molecular Neurobiology
- Director, Baltimore Huntington's Disease Center
- Director, HDSA Center of Excellence for Huntington's disease
- Member, Johns Hopkins Clinician Scientist Review Committee
Dr. Russell Margolis graduated from Princeton University with a degree in Biology in 1982, and received his M.D. degree from Johns Hopkins University School of Medicine in 1986. He completed a residency in psychiatry at Johns Hopkins in 1990. After a fellowship emphasizing neuroplasticity and pharmacology at the National Institute for Mental Health under the mentorship of Drs. Robert Post and De-Maw Chuang, he returned to Johns Hopkins as a faculty member of the Division of Neurobiology in the Department of Psychiatry in 1992. He was promoted to Assistant Professor of Psychiatry in 1993, and Associate Professor of Psychiatry in 1997, and Professor of Psychiatry in 2004. He is currently director of the Laboratory of Genetic Neurobiology and the Neurogenetics Testing Laboratory and is a faculty member of the Program of Cellular and Molecular Medicine. His research focus is on the psychiatric, genetic, and pathogenic aspects of neurodegenerative and psychiatric disorders, with a particular emphasis on diseases affecting the cerebellum and the basal ganglia.
- Affective disorders
- Cerebellar disorders
- Genetics of movement disorders
- Geriatric psychiatry
- Huntington's disease genetics and pathogenesis
- Psychiatric manifestations of neurological disorders
Dr. Wenzhen Duan is Assistant Professor in Department of Psychiatry at Johns Hopkins University School of Medicine. She received her M.D. in Medicine in 1992 and Ph.D. in Neuropharmacology in 1998 from Peking Union Medical University, China. She pursued post-doctoral research in Neurobiology of neurodegenerative diseases under Dr. Mark P. Mattson at University of Kentucky and National Institute on Aging. She joined faculty in Division of Neurobiology in 2004.
Her research interests focus on understanding pathogenesis and cell death pathways of neurodegeneration with a view to discovering new therapeutic strategies in neurodegenerative diseases with a focus on Huntington’s disease (HD) and Parkinson’s disease (PD). The research in her group includes developing cell and mouse models of HD and PD, therapeutic target identification and validation, compound screening, preclinical trials and image studies.
- Neurobiology and therapeutics of Huntington’s disease.
- Neurobiology and therapeutics of Parkinson’s disease.
- The role of neurotrophins in neurodegenerative diseases.
- Metabolic regulation in neurodegenerative diseases.
- Assistant Professor, Division of Neurobiology, Department of Psychiatry and Behavioral Sciences.
- Director, Laboratory of Translational Neurobiology.
Dr. Wanli Smith is an assistant professor in the Department of Psychiatry at Johns Hopkins University School of Medicine and the director of the Cellular Neurobiology Laboratory. She received her M.D. in clinical medicine and M.S. in pharmacology at Xi’an Medical University and her Ph.D. in biochemistry and molecular biology at the Beijing Institute of Pharmacology and Toxicology in China. She pursued post-doctoral work in cellular and molecular biology laboratories in the National Institute on Aging at the National Institute of Health and and in the Department of Psychiatry, Division of Neurobiology, at Johns Hopkins. Her lab is currently directed towards understanding the molecular pathogenesis of neurodegenerative diseases and other disorders such as obesity. Her research goal is to elucidate the molecular signaling pathways of these disorders, to identify potential therapeutic targets and to develop novel therapeutics. Dr. Smith welcomes the fellows, graduate and undergraduate students, who are interested in this research, to join her lab.
- Parkinson’s Disease
- Alzheimer’s disease
- Neuronal cell death and protein aggregation in neuropsychiatric conditions
- Director, Laboratory of Cellular Neurobiology
- Assistant Professor, Department of Psychiatry and Behavioral Sciences