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.
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