The candidate is a Neurologist with clinical and basic science training in inflammatory neuropathy. Her prior research focused on the pathogenic effects of complement in human and animal models of inflammatory neuropathy. This MCSDA proposal explores a much different role for complement in neuropathy, its potential beneficial effects on SchC recovery through upregulation of protective complement regulatory proteins (CRP) and stimulation of cell cycle entry and progression. The basis for exploring this novel role for complement in immune-mediated neuropathy derives from studies in non-neuronal cells, which suggest that terminal complement complexes (TCC) protect cells from subsequent attack by complement, upregulate protective CRP, and stimulate DNA synthesis and proliferation; events which may be crucial for recovery from inflammatory neuropathy. In spite of demyelination associated with complement deposition, the Schwann cell (SchC) appears to resist cytolysis. SchC express the full array of CRP, which may confer resistance to complement mediated cytolysis. Whereas, the relative paucity of protective CRP on the surface of myelin may account for its exquisite sensitivity to complement mediated damage. This proposal specifically investigates: a) whether sublytic complement exposure attenuates further complement mediated damage by upregulating expression of protective CRP, b) the regulatory mechanisms, which may underlie the differential CRP expression and account for the differential complement susceptibility of the SchC body and myelin membranes, and c) whether TCC induced and regulate SchC cell cycle entry and progression, facilitating recovery and eventual remyelination. We propose to investigate these mechanisms utilizing a series of in vitro SchC and SchC/DRG co-culture model experiments. Parallel studies using an animal model of inflammatory neuropathy will be used to confirm these effects in vivo. Results of these studies will extend our knowledge of the important role of complement, protecting the Schc and triggering recovery from inflammatory neuropathy. These investigations and requisite laboratory training in molecular biology, transport mechanisms, and cell cycling under the principal mentor, Dr. Moon Shin, and associated mentors Drs. Koski and Edidin, will provide an enriched interdisciplinary training environment advancing the candidate's career toward becoming an independent investigator in the area of molecular biology of protective mechanisms underlying recovery from inflammatory neuropathy.
| Hafer-Macko, C E; Dyck, P J; Koski, C L (2000) Complement activation in acquired and hereditary amyloid neuropathy. J Peripher Nerv Syst 5:131-9 |
