DESCRIPTION (provided by applicant): Magnetic resonance imaging is an important tool in diagnosing and monitoring disease activity in multiple sclerosis. MS lesions appear as bright areas on T2 weighted MRI images. In approximately 30% of MS patients, brain MRI also reveals a relatively unusual finding called T1 black holes or T1 hypointensities. Unlike the more commonly seen T2 hyperintensities, chronic T1 black holes correlate well with disability in MS. It is currently not known what is causing T1 black holes. T1 black holes are thought to represent areas of more extensive tissue damage, including axonal loss. However, since MS patients only rarely get biopsied, it is difficult to determine the cell types that are important from the standpoint of T1 black hole formation. Our team of investigators is the first to report T1 hypointensities in a viral induced mouse model of MS. Our preliminary data suggests that a specific immune cell type, the CD8+ lymphocyte, plays a key role in the formation of T1 hypointensities. In Aim 1 of this proposal, we will investigate if the transfer of these lymphocytes to transgenic animals that do not have these cells will restore the immune system's ability to generate T1 black holes. We will also investigate if typical effector molecules used by CD8+ cells, such as perforin or the granzymes are important in this process or not. We will also study whether the removal of CD8+ cells reduces the amount of T1 black hole formation. In Aim 2, we will investigate if CD8+ cells are present in tissue at areas of black hole formation. In Aim 3, we will investigate if the areas of neuronal and axonal loss corresponds with T1 black holes on MRI, and we will also investigate whether the extent of tissue loss corresponds with the volume or intensity of T1 black holes. We believe that by clarifying the mechanisms that lead to the more extensive tissue damage that characterizes T1 black holes, we will gain new insight into important immune effector pathways, which may lead to new therapies in MS. Since chronicT1 black holes are known to correlate well with disability, we may be able to more meaningfully influence disability in MS patients by understanding the immune mechanisms leading to this MRI finding. NARRATIVE: "In the proposed project, a magnetic resonance imaging (MRI) finding called "T1 black holes" is investigated. This MRI sign is known to be associated with more disabling forms of multiple sclerosis. Studying our novel animal model will allow us to understand how the immune system mediates the formation of this MRI finding, which may lead to the development of more effective therapies in MS."
|Effective start/end date||4/1/08 → 3/31/13|
- National Institutes of Health: $109,439.00
- National Institutes of Health: $270,518.00
- National Institutes of Health: $197,686.00
- National Institutes of Health: $266,969.00
- National Institutes of Health: $307,125.00