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The newspaper of The Johns Hopkins University September 20, 2004 | Vol. 34 No. 4
NARSAD Funds Nine JHU Investigators; 2004 Support Tops $500,000

The National Alliance for Research on Schizophrenia and Depression is providing more than $500,000 in 2004 to nine Johns Hopkins University researchers to study causes and treatments for mental illness.

NARSAD, the largest donor-supported organization in the world devoted exclusively to funding scientific research on psychiatric disorders, is awarding one Distinguished Investigator Award (one year/$100,000) and eight two-year Young Investigator awards ($60,000) to the Hopkins community.

The scientific leadership of NARSAD, the Scientific Council, reviewed more than 1,000 grant applications to select these current awards.

"The research NARSAD is supporting with these grants represents all phases of the leading edge of research on the human brain and mental disorders," says the council's president, Herbert Pardes, who also is president and CEO of New York-Presbyterian Hospital and professor of psychiatry at Columbia University College of Physicians and Surgeons, as well as the former vice president for health sciences of Columbia University and former director of the National Institute of Mental Health.

"Not long ago, people were looking for a single gene for each mental illness," Pardes says, "but today, as our research grants show, there is a multiplicity of genes functioning in complex relationships at the core of each of the characteristic mental illnesses. The research we are funding aims to understand this complexity and then to treat it."

Christopher Ross, professor, SOM, received a Distinguished Investigator Award to develop models for schizophrenia and other psychiatric diseases focusing on the DISC-1 gene, mutations in which can cause a rare form of schizophrenia. He plans to develop mouse models related to mutant DISC-1 using lentiviral expression methods. Using neuropathologic analyses and behavioral studies, he predicts that mutant DISC-1 will produce abnormal neuronal development resulting in abnormal neuronal morphology in the cerebral cortex, hippocampus and possibly other forebrain regions.

The Young Investigator Awards are as follows.

Susan E. Holmes, assistant professor, SOM, plans to screen a sample of individuals with schizophrenia and bipolar disorder for three of the seven genes in the so-called "14-3-3" family of proteins, which has been associated with both conditions. Several lines of genetic evidence show these genes may have a strong association with these diseases.

Francis M. Mondimore, assistant professor, SOM, will evaluate data from several hundred families who have participated in genetic studies to identify family members with chronic depression. She will then analyze the data to determine whether periods of chronic depression run in some families and not others. She will also perform genetic (or linkage) analysis to find the location of the genes responsible for putting individuals at risk for developing chronic depression. Mondimore hopes to determine if chronic depression is a marker for a genetic subtype of affective disorders such as unipolar and bipolar depression.

Jennifer L. Payne, assistant professor, SOM, aims to test whether women with mood disorders who experience hormonally triggered depressions have an underlying genetic vulnerability that differs from women with mood disorders who do not experience such depressions. These studies may lead to an identification of women at risk for hormonally triggered depressions and to new treatments for them.

Akira Sawa, assistant professor, SOM, aims to engineer transgenic mice expressing mutant DISC1 and wild-type DISC1, hoping these mice will be the first good genetic animal model of schizophrenia. Sawa predicts that once these mice are successfully produced, they will be important tools for studying schizophrenia pathogenesis and for evaluating new therapeutics.

Shanthini Sockanathan, assistant professor, SOM, notes that studies have shown that the regions of the brain affected in people with schizophrenia also usually contain retinoic acid, a key molecule involved in developmental processes within the central nervous system. He therefore will investigate whether disrupting retinoic acid signaling will mimic abnormalities seen in schizophrenia. He will genetically disrupt retinoid signaling in mice embryos and examine the outcomes of the disturbances at certain points in brain development.

Virginia L. Willour, instructor, SOM, notes that the only genome scan for obsessive-compulsive disorder that has been published to date identified one candidate region for a gene on chromosome 9p24 that met criteria for suggestive significance. Now, the Hopkins OCD Family study has collected DNA samples from 50 OCD pedigrees containing at least one pair of affected siblings, resulting in 59 independent OCD sib pairs. In the proposal, Willour aims to genotype the 50 Hopkins pedigrees using microsatellite markers on 9p24. If the 9p24 finding is not replicated, then two other suitable candidate genes, such as brain-derived neurotrophic factor or catechol-o-methyltransferase, will be chosen.

Sarah H. Ying, assistant professor, SOM, proposes studying whether dysfunction in the cerebellum alone can result in neuropsychological and psychiatric disorders. Ying suggests that the role of cerebellar dysfunction may be demonstrated in spinocerebellar ataxia type 6, an inherited condition primarily affecting the cerebellum. A study of affect and executive function in patients with the disorder is currently under way. In the planned project, Ying aims to use novel MRI processing techniques to visualize details of the cerebellum. The methods will then allow Ying to query the structural basis of affective and executive dysfunction, an important feature of psychiatric conditions, in the SCA6 disease model.

Peter P. Zandi, assistant professor, SPH, proposes to combine data from several family-based studies to generate one of the largest datasets for genetic investigations of bipolar disorder, which probably involves multiple genes in its pathophysiology. While many current approaches use genetic analysis based on single-gene methodologies with certain genes contributing a minor amount to the disease, Zandi hypothesizes his method will overcome these limitations in identifying many susceptibility genes.


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