This is a revised renewal application for a highly productive Program Project, """"""""Biomarkers and Pathogenesis of MS: From Mouse to Human,"""""""" comprised of three projects, a Statistical Core, an Animal Model/Human Tissue Bank Core and an Imaging Core that are focused on understanding mechanisms of pathogenesis of CNS inflammatory autoimmune disorders, especially multiple sclerosis (MS). Better understanding of the mechanisms of MS progression, and what underlies the continued axonal damage and drop-out would help guide development of new therapeutics for this common disease. Additionally, an urgent need exists for innovative methods to measure CNS inflammation, demyelination and axonal injury, as well as CNS repair, not only to better understand human MS pathogenesis, but also to expedite testing of novel therapeutics. A major innovation was achieved during our first five years with our development of the novel Diffusion Basis Spectrum Imaging (DBSI) which we now propose to definitively validate and carry forward to address current needs. Following encouragement and guidance from initial reviewers, we expanded our prior focus to encompass mechanistic studies of the communication between the invading inflammatory cells and resident cells in the CNS, leading to loss of blood-brain barrier integrity. State-of-the-art imaging modalities will be used. The three P01 projects are linked thematically with the goals of defining the interface between blood-brain barrier signaling and immune cell entry and how this impacts the development of persistent inflammatory lesions, and axonal pathologies. The latter, in particular, may underlie progressive MS. Each project uses all three Cores that provide statistical, animal model/human tissue bank, imaging and administrative support. Overall objectives are to (1) develop and test novel cutting edge noninvasive and specific MRI biomarkers of white matter injuries using animal models, human tissues, and MS patients;and (2) to address and target the mechanisms by which changes in vascular permeability impact leukocyte activation and entry into CNS.

Public Health Relevance

(Overall PPG) MS affects over 2 million persons worldwide, and about one person in a thousand in the U.S. The cause of MS is not understood. Thus far, there is no cure for MS. Studying this chronic disease of the brain, spinal cord and optic nerves is challenging, because the disease changes over time. It often becomes progressive, a stage of MS for which there are no good treatments. A major impediment to a better understanding of MS is that investigators rarely obtain tissue samples for study, because to perform biopsies of the brain or spinal cord has potential to cause harm. This Program Project brings together 12 investigators in a research design comprised of three Projects and supported by three Cores to address several current needs in the field of MS. Our projects are designed to integrate with one another, with an ultimate focus on human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS059560-06A1
Application #
8735487
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Utz, Ursula
Project Start
2007-07-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$1,237,891
Indirect Cost
$425,716
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lin, Tsen-Hsuan; Chiang, Chia-Wen; Perez-Torres, Carlos J et al. (2017) Diffusion MRI quantifies early axonal loss in the presence of nerve swelling. J Neuroinflammation 14:78
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Daniels, Brian P; Klein, Robyn S (2015) Knocking on Closed Doors: Host Interferons Dynamically Regulate Blood-Brain Barrier Function during Viral Infections of the Central Nervous System. PLoS Pathog 11:e1005096
Wang, Yong; Sun, Peng; Wang, Qing et al. (2015) Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. Brain 138:1223-38

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