This is a new Program Project to expand and perpetuate the long-standing collaborative research of a highly integrated group of investigators with common interest in understanding CNS autoimmunity. Past collaborations of this group have led to more than 20 co-authored manuscripts investigating the underlying mechanisms of CNS inflammation and white matter injury. Collectively, the group developed a novel approach to use diffusion tensor imaging (DTI) for noninvasive detection and differentiation of axonal and myelin damage and then validated the method in animal models. In this PPG, communication between the invading inflammatory cells and resident cells in the CNS and the perivascular regulation of mononuclear cell infiltration will be examined with noninvasive DTI methods and with advanced histology. The PPG goals are to understand the pathogenesis of CNS autoimmunity, in particular MS, and assess the DTI biomarkers of injury in both animal models and patients. Several of the PPG investigators comprised a team that was one of the first three centers to receive the National MS Society's Collaborative MS Research Center award in 2003. This Syr, non-renewable Award will end in Winter 2008. Proj 1 "Assessing MRI Biomarkers of White Matter Injury" is directed by SK Song, whose team will use three models of white matter injury to determine the sensitivity of the MRI biomarkers of CNS white matter injury and assess the use of these biomarkers as the surrogate endpoint to evaluate therapeutic efficacy of EAE and prognosis of SCI. Proj 2 "Neuroprotective mechanisms of CXCL12 in CNS demyelinating diseases" is directed by R Klein, an established researcher on roles of chemokines in experimental viral models and EAE. Proj 2 will determine how CXCL12-mediated perivascular localization regulates mononuclear cell trafficking into CNS in both rodent and human autoimmune diseases, how perivascular localization regulates mononuclear cell activation during CNS autoimmunity, and how CXCL12 regulates remyelination. Proj 3 "CNS and lymphocyte interactions regulating inflammation" is directed by J Russell. Recent work from his laboratory has found that TNFR1 responses of astrocytes are key in promoting infiltration of the parenchyma which is in turn critical for EAE severity. Using animal models he has developed, the sensitivity of DTI biomarkers will be tested. Astrocyte responses in different CNS regions to a variety of cytokine environments and Th1 and Th17 cell trafficking will be examined using Gd-enhanced MRI and DTI. Proj 4 "Directional Diffusivity as a Window into the Pathology of MS," directed by A. Cross, will translate findings from Projects 1, 2, and 3 to humans. The feasibility of using DTI to discern pathology in the white matter tracts of brains and spinal cords of living humans will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS059560-05
Application #
8322119
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Utz, Ursula
Project Start
2008-09-25
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$992,711
Indirect Cost
$382,300
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lin, Tsen-Hsuan; Spees, William M; Chiang, Chia-Wen et al. (2014) Diffusion fMRI detects white-matter dysfunction in mice with acute optic neuritis. Neurobiol Dis 67:1-8
Lin, Tsen-Hsuan; Chiang, Chia-Wen; Trinkaus, Kathryn et al. (2014) Manganese-enhanced MRI (MEMRI) via topical loading of Mn(2+) significantly impairs mouse visual acuity: a comparison with intravitreal injection. NMR Biomed 27:390-8
Wang, Xiaojie; Cusick, Matthew F; Wang, Yong et al. (2014) Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice. NMR Biomed 27:843-52
Chiang, Chia-Wen; Wang, Yong; Sun, Peng et al. (2014) Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage 101:310-9
Tu, Tsang-Wei; Budde, Matthew D; Xie, Mingqiang et al. (2014) Phase-aligned multiple spin-echo averaging: a simple way to improve signal-to-noise ratio of in vivo mouse spinal cord diffusion tensor image. Magn Reson Imaging 32:1335-43
Cruz-Orengo, Lillian; Daniels, Brian P; Dorsey, Denise et al. (2014) Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest 124:2571-84
Lin, Tsen-Hsuan; Kim, Joong Hee; Perez-Torres, Carlos et al. (2014) Axonal transport rate decreased at the onset of optic neuritis in EAE mice. Neuroimage 100:244-53
Durrant, Douglas M; Daniels, Brian P; Klein, Robyn S (2014) IL-1R1 signaling regulates CXCL12-mediated T cell localization and fate within the central nervous system during West Nile Virus encephalitis. J Immunol 193:4095-106
Williams, Jessica L; Patel, Jigisha R; Daniels, Brian P et al. (2014) Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system. J Exp Med 211:791-9
Spees, William M; Lin, Tsen-Hsuan; Song, Sheng-Kwei (2013) White-matter diffusion fMRI of mouse optic nerve. Neuroimage 65:209-15

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