My long-term goal is to elucidate the cellular and molecular mechanism by which MerTK exerts its effects on phagocytosis of the retina pigmental epithelium (RPE) cell. MerTK is a receptor-type protein tyrosine kinase, belonging to the TAM family. MerTK knockout mice develop autoimmune disease, retinitis pigmentosa (RP) in adults with characterization of defective phagocytosis of the apoptotic lymphocytes and spent retinal outer segments (OS) by macrophage and RPE cells, respectively. Photoreceptor degeneration caused by a failure of the RPE phagocytosis has been observed and intensively studied in the Royal College of Surgeons (RCS) rat, a model in which the RPE cells carry a MerTK null mutation. MerTK null also causes human RP. Both in vivo and in vitro studies showed that the MerTK receptor participated during OS ingestion. However, the molecular mechanism on how the MerTK regulate RPE phagocytosis is still not very clear. We have analyzed gene expression profile in MerTK mutant RPE and performed functional studies on the affected genes. Of those, the PTTG was dramatically upregulated by MerTK mutation and knockout one copy of PTTG in the MerTK-/- RPE partially prevented photoreceptor degeneration in vivo. We will select and focus on MerTK mediated gene regulation to study its functional role in regulation of phagocytosis. In this proposal, we project to study how the MerTK regulate PTTG and whether the PTTG affect RPE phagocytosis. We will also investigate whether structural preservation of the central photoreceptor by lower PTTG is corresponding to function recovery with ERG or OKR measurements. Our investigation will aid in one step forward to understand the molecular mechanism on the MerTK regulation of RPE functions.
Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases with a worldwide prevalence of 1:3000 and a leading cause of inherited blindness. RP is caused by mutation in a group of unrelated genes, one of these is MerTK. Our experiments in this proposal aim to elucidate the molecular mechanism of the MerTK regulation on RPE phagocytosis through studies of one candidate gene under MerTK regulation, which may in turn affect RPE function. The data from these studies is expected to provide us the new knowledge and understanding of the RPE function, which will allow us to develop and implement new therapies for treatment of RP caused by RPE dysfunction.
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