The applicant is now finishing his residency training in Neurology. Prior to this residency, he was involved in basic research and gained significant experience in molecular genetics. He made several contributions to research of genetic causes of motor neuron disease and related disorders. He is changing his main research focus to multiple sclerosis (MS), and proposes to develop transgenic mouse model for MS with doxycycline-controllable expression of interleukin-3 (IL-3) in astrocyte. The proposal is based on the previous observation that constitutive over-expression of IL-3 in astrocytes of GFAP-IL3 transgenic mice causes microglia/macrophage-mediated demyelination that resembles MS. The control of IL-3 expression will permit to overcome several limitations of GFAP-IL3, including toxicity of IL-3 to developing brain and allow the analysis of various conditions of expression of the transgene. The candidate will analyze clinical and pathologic aspects of the disease with varying levels of expression and host-age at initial induction of IL-3. Progression patterns after discontinuation of IL-3 expression in symptomatic mice will be analyzed. Analysis of cytokine and chemokines expression by RNase protection assay, and of gene expression by gene microchips assay will determine the molecular cascade (s) involved in demyelination. These findings may be relevant to MS. The candidate will dedicate 75% of his time to research and 25% to clinical activity. He will be developing his skills in immunology and will be working closely with Dr. Lipton who has extensive experience in experimental animal models of demyelination. The candidate's long-term plan is to establish an independent research program focused on the development of genetic animal models for MS and the study of the role of macrophage and microglia in the genesis and the progression of CNS demyelination.
