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Vanderbilt Department of Neurology

Basic Research Summary of the Neuroimmunology Program

A) LPS induced model of primary demyelination.

1. The laboratory is currently funded to examine novel models of demyelination that reflect multiple sclerosis (MS). We have been studying the immunopathological features of demyelination induced by the direct injection of lipopolysacharride into the corpus callosum of rats. The lesions that develop in this model closely reflect the lesions of Type III oligodendrogliopathy that is seen in a subset of patients with MS. The lesions have features of, myelin loss in the absence of any infiltrating T cells. In collaboration with the neuroimaging institute, we are examining the MRI metrics of the lesions that is able to specifically correlate with the demyelination.

2. In dissecting the role of biochemical markers that are likely to play a role in the demyelination the laboratory has been examining the induction of nitric oxide synthase (NOS) and in particular nNOS (neuronal NOS) as mediators of oligodendrocyte injury.

3. In attempting to reverse the demyelinating lesions we are also examining the efficacy of neuroprotective agents in preventing LPS induced demyelination. While these studies are currently being carried out on primary oligodendrocyte cultures and in transformed oligodendrocyte cell line, we will be extending these ideas to in vivo models of demyelination.

B) Role of p53 pathway in MS

1. Since beta Interferon has been one of the front line drugs in MS, we have studied the mechanism of action of beta interferon in the regulation of the p53 pathway. We have found that p53 is rapidly induced in peripheral mononuclear cells and induces cell cycle arrest. We have concluded that one of the key mechanism of action of beta IFN is perhaps through the induction of p53.

2. Our more recent studies have uncovered that there are at least 9 different isoforms of p53 that are induced by p53. We are currently investigating the mechanism of action of the different p53 isoforms in the regulation of key molecules that play a role in cell cycle arrest and apoptosis.

C) Role of infectious agent in MS.

1. In collaboration with the department of Pathology and microbiology we are studying the role of C. pneumoniae in MS. We have developed a sensitive assay to detect the presence of C. pneumoniae genes in the spinal fluid of MS patients. We are expanding the specificity and sensitivity of these tests to larger samples and include patients with other neurological disease.

Research Papers published 2007-2009:

1. Pawate, S., H. Moses, and S. Sriram, Presentations and outcomes of neurosarcoidosis: a study of 54 cases. QJM, 2009. 102(7): p. 449-60.

2. Tang, Y.W., et al., Qualitative and quantitative detection of Chlamydophila pneumoniae DNA in cerebrospinal fluid from multiple sclerosis patients and controls. PLoS One, 2009. 4(4): p. e5200.

3. Yao, S.Y., M. Soutto, and S. Sriram, Bacterial cell wall products increases stabilization of HIF-1 alpha in an oligodendrocyte cell line preconditioned by cobalt chloride or desferrioxamine. J Neuroimmunol, 2008. 200(1-2): p. 17-26.

4. Yao, S.Y., M. Soutto, and S. Sriram, Preconditioning with cobalt chloride or desferrioxamine protects oligodendrocyte cell line (MO3.13) from tumor necrosis factor-alpha-mediated cell death. J Neurosci Res, 2008. 86(11): p. 2403-13.

5. Zhang, Fang Lin, S. Sriram. Regulation of p53 by beta Interferon. Immunology. 2009, (in press).

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