Collaborative MS Research Center Award
$825,000; 4/1/05-3/31/10
Principal Investigator
Jorge R. Oksenberg, PhD
University of California at San Francisco
Collaborators
Parvin Mousavi, PhD
Queen's University, Kingston, Ontario
Daniel Pelletier, MD
Sergio Baranzini, PhD
University of California at San Francisco
David Mohr, PhD
Northwestern University, Evanston, IL
Purpose
To combine novel technological and analytical approaches for the discovery of molecules that may be used as "markers" to predict progression of disease in multiple sclerosis.
Summary
MS is a highly unpredictable disease. Not only are the symptoms or even timing of attacks unpredictable, there are no laboratory or clinical tests that can predict the future course of the disease.
Jorge R. Oksenberg, PhD—who has been involved in MS genetics for more than a decade—has gathered a team to integrate state-of-the-art magnetic resonance imaging (MRI) technology, molecular biology techniques, and clinical information to develop a unique approach to predicting MS progression. The approach is based on the hypothesis that MRI images reflect specific molecular and cellular events that occur as the blood-brain barrier (BBB, the lining of cells that protects the brain) is breached in MS. Changes in the activity of these molecules and cells may precede MRI-detected abnormalities, and may be used as "markers" to predict them.
To test these ideas, Dr. Oksenberg's team is collecting and analyzing MRI data and blood samples taken every two months from a group of 112 well-studied persons with MS. These participants are being recruited by psychiatrist David Mohr, PhD, and MRI specialist Daniel Pelletier, MD as part of an NIH-funded study seeking to discover MRI changes associated with stress. Dr. Mohr is collecting clinical information on the rate of relapses, progression of disability, and neuropsychological impairment. Dr. Pelletier is acquiring and analyzing the MRI data, extracting information on lesion volume, tissue loss, changes in brain tissue volume, and other characteristics.
Using blood samples taken at the beginning of the study, genetics specialist Sergio Baranzini, PhD, is using microarray technology, which allows for the analysis of thousands of genes at once, to evaluate the activity of more than 21,000 genes in the blood of the participants. The group will look at the activity of these genes in blood samples collected by Dr. Mohr on the day of each MRI scan.
Dr. Oksenberg will screen the blood sample using mass spectrometry, which can identify thousands of proteins at once. He is seeking to identify the molecules associated with increased gene activity. This strategy, known as proteomics, aims at identifying the molecular biomarkers much needed in MS for monitoring disease progression and responses to therapy.
The changes in gene expression and proteomics are being correlated with clinical endpoints of interest, such as type of therapy, EDSS scores (which measure disability), and number of relapses. The information will be integrated in a computer model with the expertise of Parvin Mousavi, PhD, a talented computer scientist.
Dr. Oksenberg and colleagues are attempting to develop an updated model of the molecular dynamics of how myelin and other nerve tissues are damaged, and how MS develops and progresses. He has assembled a truly multidisciplinary team with outstanding expertise in MS clinical care, biomedical imaging, molecular biology, and advanced statistics and data mining, to accomplish this goal.
Recent Progress
Dr. Oksenberg’s team has made substantial progress in developing fast and efficient methods of analysis that will be applied to a longitudinal dataset of people with MS. They reported in the April 15, 2007 Journal of Immunology on using DNA microarrays gene chips that can analyze thousands of genes at once to analyze the genetic response to interferon treatment in people with MS.
These studies are sure to increase our understanding of MS development and treatment response.