Mark Fields, Ph.D., M.P.H.
Principal Investigator, Mark Anthony Fields, Ph.D., M.P.H.
SUMMARY OF LABORATORY RESEARCH
Cell transplantation is a promising therapeutic approach for the replacement of degenerated retinal cells in patients with dry or nonexudative age-related macular degeneration (dry AMD), retinitis pigmentosa, Stargardt’s disease and other retinal degenerations. In these disorders loss of vision is due to degeneration and death of photoreceptor cells in the retina. Early in the course of retinal degenerations, it may be possible to intervene with growth factors or gene therapy to maintain or restore photoreceptor function and prevent cell death; however, it is not likely that patients with advanced dry AMD and hereditary retinal degenerations will benefit from this approach. In advanced cases, treatment of retinal degeneration will require replacement of dysfunctional or dead cells with transplanted cells. Thus, it is important to develop techniques to generate retinal photoreceptors from human embryonic stem cells, and to transplant these cells into the subretinal space in animal models prior to successful therapy in patients.
My overall goal is to seek to identify the critical factors involved in photoreceptor differentiation and then modulate expression of these regulators for use in stem cell based therapies. Specifically, I seek to understand the role of transcription factors such as cone-rod homeobox (Crx), orthodenticle homeobox 2 (Otx2), neural retina leucine zipper (Nrl), neurogenic differentiation 1 (NeuroD1) and neurogenic differentiation 4 (NeuroD4) which are known to be involved in photoreceptor development and their use in the development of photoreceptors from embryonic stem cells. I also seek to understand the developmental cues that allow embryonic stem cells to differentiate to rod photoreceptors in vitro and in vivo.
The above is accomplished through the use of microarray analyses of developing mouse retinas in order to identify key genes involved in rod photoreceptor differentiation and timing of gene expression. Expression vectors that allow for the replication of developmental genes are also used to induce embryonic stem cells to differentiate into rod photoreceptors in vitro. Techniques that allow embryonic stem cells to differentiate to photoreceptors under defined culture conditions are also applied. Successful differentiation of stem cells in culture will ultimately be tested in animal models of retinal degeneration through the transplantation of cells into the subretinal space of diseased retinas. Successful transplantation of cells in animal models of retinal degeneration will lead to the understanding of retinal diseases and the development of stem-cell-based therapies in humans.