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Collaborative Initiative Focuses on Neurological Disease
July 8, 2005
By Elizabeth Tolchin

In addition to being an exercise in creating a way for researchers to collaborate across distant locations over a shared infrastructure, the Biomedical Informatics Research Network (BIRN) is creating one of the most technologically advanced studies of human neurological disorders.
Currently the BIRN involves a consortium of 19 universities and 26 research groups that participate in one or more of the three test bed projects centered around brain imaging of human neurological disorders and associated animal models.

The three test bed projects are Functional BIRN, which focuses on finding the causes of schizophrenia and developing treatments; Brain Morphometry BIRN, which is performing large-scale analysis of patient population data to investigate whether brain structural differences correlate to symptoms such as memory loss or depression and if specific structural differences distinguish diagnostic categories; and Mouse BIRN, which studies animal models of several neurological disorders and is working to integrate structural and functional data with genomic and gene expression data on the mouse brain.

Arthur Toga, PhD, professor of neurology, University of California, Los Angeles, is the principal investigator on the Mouse BIRN project. “The goal of Mouse BIRN is to generate an anatomical atlas of a particular [widely studied] strain of mouse brain where we can map gene expression data into that anatomy in a way that allows one to make genotype/phenotype comparisons,” says Toga. This system, he says, would then be applied to a particular disease process such as multiple sclerosis or Parkinson’s disease, which often have a genetic component to them. “With this system our animal models will allow us to make direct measurements of the anatomy-to-genetic relationship.”

Rather than using microarrays to analyze the gene expression of the mouse brain Toga’s group is using imaging technology along with in situ hybridization. “Arrays don’t tell you exactly where you are and genes turn on and off in response to a variety of stimuli, many of which are environmental,” says Toga, “so it is important to be able to equate the activities and behaviors at the genetic level with what is going on at the circuit or systems level of the brain. It is conceivable that you would be able to better understand the cascade of events that occurs all the way from molecules to mind, if you had the capacity to relate genetics and anatomy.”

The diseases are induced in the mouse in a variety of ways and the animals will be compared with the normal mouse brain atlas, which is regularly updated. “The mouse brain atlas was originally developed using high-field MRI of the mouse. These very detailed images form the framework for other characterizations of the anatomy, which are made through traditional histological techniques. All of the information that is gathered is placed in the same coordinate system and the result is an atlas that is comprised of multiple modalities,” says Toga, “from MRI, through histology, and ultimately gene expression data.”

They currently have atlases for Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. “The reason we chose those was because it gives us a survey across white matter and gray matter,” says Toga. “Second, these are degenerative processes that change over time so we can look at the progression of the disease process. Third, there are reasonably accepted animal models of each of these diseases to the human condition. Finally, the relationship between Alzheimer’s disease, in particular, gives us a close linkage with Morphometry BIRN, which uses Alzheimer’s disease as its test bed.”

Much of the work, he says, is in the development of tools and infrastructure to carry out these studies. “Populating it with another animal or another set of data should be straightforward if the tools are appropriately built. The primary focus is to build the tools, but you can’t build the tools unless you can say that they work well, so we have identified these three test beds not to discover the fundamental basis of the neuropathology but, rather, to test the efficacy of the tools.”

The Mouse BIRN project formally began about three years ago. Each of the participants in the Mouse BIRN has a history of developing related science that could be leveraged in a cooperative way to jumpstart the BIRN effort, says Toga. “The time line has been for the development of an interface and atlas/database so that new users can make queries on the data and visualize it through the atlas. This technology is functional and operational now.”

The main challenge, he says, is dealing with the diverse sets of data that come from the different laboratories and the ability to accommodate that data. Diversity can come in the form of file format as well as in the data quality or comprehensiveness.

The next phase, says Toga, is to develop a much more comprehensive set of tools that allow the importation of unique data sets from other laboratories and then to test the utility of the tools against these test beds. This next phase was recently funded by the National Center for Research Resources of the National Institutes of Health and activated as of April 2005.

“I look forward to the day when a user can download this package and, by pressing a button, they can upload their own set of gene expression data, register it, see a display of the relationship, and get a quantitization of the concentration of gene expression mapping relative to a particular system,” Toga says. “To me that is a leap forward in the way we do neuroscience.”

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