During development, intrinsic genomic mechanisms of commitment and lineage restriction are modulated by environmental signals in both embryonic and postnatal cells. Studies utilizing neural cells in culture and neural cell transplants have been instrumental in assessing the potential of cell grafts for CNS repair. We have previously demonstrated in a rat model in assessing the potential of cell grafts for CNS repair. We have previously demonstrated in a rat model that direct intraparenchymal delivery of specific factors known to participate in myelinogenesis, in combination with OL transplants, may provide the most promising approach for therapy of myelin deficiency. We have also shown in vivo that Tf in combination with bFGF has a synergistic effect on OL and myelin gene expression in the normal and the myelin deficient rat brain. These data, in addition to the rapid advances in our understanding of stem cell biology, offer a more promising future for the development of cell replacement therapies in dys- and de-myelinating diseases in humans, which often manifest as debilitating development and/or adult disabilities and mental retardation. We propose to build on our previous results by further investigating the effects of IGF-1 and bFGF in combination with PDGF and Tf on remyelination in both the md rat and the 4e Tg mouse. To overcome possible limitations arising from the short half-life of PDGF, we will generate a stable cell line engineered to continuously secrete PDGF. These cells will then be grafted into the brain parenchyma of both the md rat and 4e Tg mouse in combination with the growth factor(s) mentioned above. In addition, we propose developing OL precursors from mouse stem cells and ES cells, which will provide a plentiful and reproducible population appropriate for transplantation into the 4e demyelination model. Using rat stem cells in a parallel approach, we will further develop and characterize OL precursor for transplantation into the md rat. Although we have successfully demonstrated the migration and integration of grafted OL progenitors, additional specific neurologic assessments and ultrastructural studies are necessary in order to evaluate the effects of the combined treatments of the md and the 4e animal models. The combined data derived from these studies will have direct relevance to future clinical research directed at re-myelinating the affected CNS of both inherited and acquired disorders, e.g. Pelizaeus Merzbacher's disease, spinal cord injury, traumatic brain injury, and AIDS dementia.
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