This is a re-submission of a proposal last reviewed in October of 1994. The theme of the proposed studies is to develop glial cell transplant strategies in animal models of inherited or acquired demyelinating diseases. The overall goal is to determine the feasibility for producing global remyelination of the central nervous system (CNS). Strategies to be tested will involve neonates and adults, some scenarios including the presence and effects of inflammation and gliosis. Experimental outcome is to be monitored histologically by re-acquisition of normal myelin content and functionally by electrophysiological assessments. The primary criticisms cited in the previous review involved concerns over the diffuse nature of the investigation as it pertained to numerous experimental animal models of demyelination, as opposed to performing more in-depth analyses of one or two models. In addition, the previous review cited an apparent lack of obvious extension that was proposed in relation to work already accomplished and a lack of experimentation that might be considered more directly relevant to human disease. Moreover, the investigators were advised to focus experimental outcome more on the restoration of neuronal conductance, rather than MRI analyses, which should allow a more direct assessment of relevant physiological effects on neurotransmission. In response to the previous critique, Dr. Duncan has provided more information concerning the value of each experimental model with which he plans to work, some in the form of recent publications. He has removed the majority of analyses involving MRI, now favoring electric conductance studies as suggested by the last review. Although little attention is to be paid to allo-engraftment, more emphasis is to be placed on adult transplantation, making the studies somewhat more relevant to various human scenarios. Thus, the Specific Aims of the proposal are:
Specific Aim 1 : Demonstrate dissemination of transplanted cells and large-scale remyelination. The feasibility of producing widespread dissemination of transplanted cells through the ventricular system and subsequent invasion of the neuropil will be tested by injecting oligodendrocyte progenitors into the lateral ventricle of adult, neonatal and fetal mutant rats. In addition, this will be carried out in a chronic experimental allergic encephalomyelitis (EAE) model. Dissemination of cells will also be attempted via the sub-arachnoid space of the spinal cord. Multifocal injection of similar cells into contiguous spinal cord segments will be performed to determine whether a continuous column of remyelination extending along several spinal cord segments can be achieved.
Specific Aim 2 : Determine whether inflammation and gliosis inhibit or prevent remyelination by transplanted glial cells. Animal models in which inflammation and/or chronic gliosis are prominent are to be used as recipients of transplanted glia, and the migration and myelination by the transplanted cells in and through pathological areas will be determined. For example, in the chronic EAE model to be used, focal implantation of cells will be used to examine whether such cells will migrate through a normal neuropil towards focally demyelinated plaques. In addition, transplantation into areas of chronic demyelination is hoped to determine whether axons can be successfully remyelinated after prolonged periods of non-ensheathment.
Specific Aim 3 : Determine the functional effect of glial cell transplantation. Glial cell transplantation in neonatal and adult demyelination mutants is to be followed by tests of physiological function. This is to be a collaboration between Dr. Duncan and Dr. Kocsis at Yale University, who will perform the electrophysiological measurements.
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