Multiple Sclerosis (MS) is a devastating autoimmune demyelinating disease of the central nervous system (CNS). Inflammation and neurodegeneration contribute to disease symptoms that include motor dysfunction and vision problems. Untargeted metabolomics performed on tissue from human MS patients and animal models of MS has uncovered upregulation of multiple acylcarnitine species in CNS tissue. These results suggest that perturbations in fatty acid metabolism occurs in response to inflammation and demyelination. This proposal will further characterize the role these metabolites play in potentiating inflammation or tissue injury using mass spectrometry, imaging, and molecular biology techniques. Furthermore, acylcarnitines or other upregulated metabolites will be examined in CSF for their potential use as biomarkers for inflammatory attacks in the CNS.
Aim 1. Determine what cell types in the CNS upregulate acylcarnitine production in response to inflammation and demyelination. The localization of multiple acylcarnitine species to inflammatory lesions will be examined in situ using mass spectrometry-based imaging and in isolated immune and CNS cells with ESI-TOF mass spectrometry. The expression of key enzymes involved in fatty acid metabolism will be determined in spinal cords in EAE, MHV, and MS tissue.
Aim 2. Fatty acid synthesis will be inhibited during EAE using orlistat and C75. Beta oxidation will be inhibited with etomoxir to determine the effect of altering fatty acid metabolism of T cell function in the CNS and periphery.
Aim 3. Determine if acylcarnitine species are found in the CSF of patients undergoing disease relapse and whether these metabolites can be a marker for disease activity in MS or if upregulation is a general phenomenon during neurologial disease. In addition other metabolites that show changes in MS tissue will be identified in CSF to determine if they would be biomarkers for MS diagnosis.
This work has important implications for diagnosis and treatment of MS. Current therapies are not effective for all patients or have significant side effects. If alterations in fatty acid metabolism affect disease pathogenesis, drugs that are currently available could be used for MS treatment. Furthermore the identification of biomarkers would facilitate early diagnosis and testing of new therapies.
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