The long-term goal of this research is to define the roles of selected chemokines in central nervous system (CNS) inflammatory responses involving monocytes, macrophages and lymphocytes. Chemokines are small pleiotropic chemoattractant cytokines that mediate inflammatory, angiogenic and growth-regulatory functions. We propose to define the roles of two chemokines, monocyte chemoattractant protein-lalpha (MCP-1alpha) and macrophage inflammatory protein-lalpha (MiP-lalpha) in the induction of inflammation in the CNS. To achieve this goal, we will use the powerful and well-characterized models that are relevant for human disease, namely experimental autoimmune encephalomyelitis (EAE) and spinal cord contusion injury (SCI). We will determine molecular, histological and behavioral characteristics of the models in genetically altered mice that are 'knocked-out' for MCP-1 or MIP-lalpha ligands or receptors, or that overexpress these chemokines in the CNS. The data gained in these studies will provide insight into the pivotal roles of chemokines and their target cells in injury responses of the CNS. It is essential to understand how these important chemokine mediators are expressed in relation to development of pathologic states. We will demonstrate how varied stimuli converge to regulate chemokine expression by CNS cells, using two incisive models of chemokine gene regulation: Theiler's murine encephalomyelitis virus (TMEV) infection of the CNS of wild-type and cytokine-knockout mice; and a defined tissue-culture system.
The Specific Aims address: 1. Role of CC chemokines in experimental autoimmune encephalomyelitis. 2. Regulation of chemokine expression during TMEV-induced inflammation. 3. MCP-1 and its receptor in spinal cord contusion injury. 4. Regulation of MCP-1 transcription by constitutive and inducible factors. Data gained from these experiments will provide a rational foundation for strategies to modulate chemokine expression during neurological disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032151-05
Application #
2622175
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Kerza-Kwiatecki, a P
Project Start
1994-05-01
Project End
2002-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Katoh, Mitsuhiko; Wu, Bao; Nguyen, Huy Bang et al. (2017) Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation. Sci Rep 7:4942
Gyoneva, Stefka; Ransohoff, Richard M (2015) Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci 36:471-80
Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S et al. (2014) Ontogeny and functions of central nervous system macrophages. J Immunol 193:2615-21
Liu, Liping; Li, MeiZhang; Spangler, Lisa C et al. (2013) Functional defect of peripheral neutrophils in mice with induced deletion of CXCR2. Genesis 51:587-95
Schafer, Dorothy P; Lehrman, Emily K; Kautzman, Amanda G et al. (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691-705
Veenstra, Mike; Ransohoff, Richard M (2012) Chemokine receptor CXCR2: physiology regulator and neuroinflammation controller? J Neuroimmunol 246:1-9
Mizutani, Makiko; Pino, Paula A; Saederup, Noah et al. (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol 188:29-36
Engelhardt, Britta; Ransohoff, Richard M (2012) Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 33:579-89
Kang, Zizhen; Liu, Liping; Spangler, Roo et al. (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32:8284-92
Li, Meizhang; Hale, James S; Rich, Jeremy N et al. (2012) Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair. Trends Neurosci 35:619-28

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