My persistent goal has been the pursuit of therapeutic interventions for patients with devastating neurologic diseases. My specific goal during the time of this award period will be on the development of selective immunotherapy for autoimmune neurologic disease. With Dr. Lawerence Steinman as my mentor I will be focusing on developing selective immune therapy for multiple sclerosis (MS), a chronic disease of the central nervous system affecting approximately 250,000 Americans. Using experimental autoimmune encephalomyelitis (EAE) in mice as a model for MS and DNA vaccination as a tool for generating an immune response, I propose to answer several questions pertaining to protective immunity against EAE. I will also use DNA vaccination as a tool in constructing a model for neurologic paraneoplastic disease. During the term proposed by this application I will attempt to address the following specific aims. (1) How general is the phenomenon of the Th2 response, a unique immunosuppressive response which occurs when EAE is prevented by injection of DNA encoding the Vbeta8.2 region of T-cell receptor (TCR)? (2) Will DNA vaccination to another variable region of the TCR, specifically Vbeta17 in SJL mice, also produce this unique Th2 response? (3) Can we enhance protection against EAE using DNA vaccination with tandem constructs containing IL-4 or IL-10 and Vbeta8.2? (4) Can we protect against EAE using DNA vaccination with myelin basic protein (MBP), MBP peptide, or MBP altered peptide? (5) Can we construct a model of neurologic paraneoplastic disease using DNA vaccination with antigens recognized by sera from patients with paraneoplastic syndromes? These experiments will be carried out at the Stanford University Beckman Center. This center, as well as the university, has a long reputation of highly respected scientific investigation and production of well- trained scientists who have become leaders in their respective fields. During the course of the proposed award period I will also continue to practice clinical neurology on a 10 percent basis and take formal coursework in basic immunology and the ethical conduct of research. The overall goal of the proposed training program is in preparing this candidate to establish an independent laboratory in an academic neurology department.
| Karpuj, M V; Garren, H; Slunt, H et al. (1999) Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei. Proc Natl Acad Sci U S A 96:7388-93 |
