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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Utz, Ursula
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Washington University
Schools of Medicine
Saint Louis
United States
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Agner, Shannon C; Klein, Robyn S (2018) Viruses have multiple paths to central nervous system pathology. Curr Opin Neurol 31:313-317
Adusumilli, Gautam; Trinkaus, Kathryn; Sun, Peng et al. (2018) Intensity ratio to improve black hole assessment in multiple sclerosis. Mult Scler Relat Disord 19:140-147
Spees, William M; Lin, Tsen-Hsuan; Sun, Peng et al. (2018) MRI-based assessment of function and dysfunction in myelinated axons. Proc Natl Acad Sci U S A 115:E10225-E10234
Zhan, Jie; Lin, Tsen-Hsuan; Libbey, Jane E et al. (2018) Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy. Front Neurosci 12:77
Klein, Robyn S; Garber, Charise; Howard, Nicole (2017) Infectious immunity in the central nervous system and brain function. Nat Immunol 18:132-141
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
Cross, Anne H; Song, Sheng-Kwei (2017) ""A new imaging modality to non-invasively assess multiple sclerosis pathology"". J Neuroimmunol 304:81-85
Klein, Robyn S; Hunter, Christopher A (2017) Protective and Pathological Immunity during Central Nervous System Infections. Immunity 46:891-909
Hou, Jianghui; Baker, Lane A; Zhou, Lushan et al. (2016) Viral interactions with the blood-brain barrier: old dog, new tricks. Tissue Barriers 4:e1142492
Salimi, Hamid; Cain, Matthew D; Klein, Robyn S (2016) Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics 13:514-34

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