DESCRIPTION (provided by applicant): The candidate, Konstantin Balashov, M.D., Ph.D., is an assistant professor of neurology at the University of Medicine and Dentistry of New Jersey. He is trained both in clinical neurology and human immunology. His immediate goal is to study the role of plasmacytoid dendritic cells (pDCs) and interferons in multiple sclerosis (MS) at a molecular level. His long-term career goal is to obtain the skills and experience necessary to develop into a funded independent clinical investigator with expertise in modern methods of immunology and genomics to study the pathophysiology of MS. The proposed five-year research training will provide skills for him in important aspects of patient-oriented research in MS. He will enhance his knowledge of biostatistics and genomics through formal coursework and supervision. He will learn the molecular biology and immunology of interferons under the guidance of Dr. Sidney Pestka. He will learn how to apply this knowledge to MS under the mentorship of Dr. Suhayl Dhib-Jalbut. The research project will capitalize o recent scientific progress in studies of pDCs, professional antigen-presenting cells, which secrete high amounts of chemokines which attract Th1 cells, and interferon-alpha which promotes generation of Th1 cells. pDCs can be activated by specific molecular patterns present in viral components through Toll-like receptors (TLRs). It is hypothesized that activation of pDCs by TLR agonists induces the generation of immunopathogenicThl cells and is associated with clinical exacerbation in MS patients. Interferon gamma, the Th1 type cytokine, and viral infections were shown to be linked to clinical exacerbation in MS. Thus, pDCs may be the key element connecting viral infection and clinical exacerbation in MS patients. Dr. Balashov will apply modern methods of genomics and proteomics to identify expression of thousands of genes and production of multiple cytokines in small cell population of pDCs isolated from MS patients. This will help to link activation of pDCs and clinical exacerbation in MS patients. Relevance: If the above hypothesis is true, small molecular substances called TLR antagonists could be tested as a new promising treatment for multiple sclerosis. TLR antagonists would prevent activation of plasmacytoid dendritic cells by viral pathogens and, therefore, the clinical exacerbation of the disease.