Transcriptional silencing in damaged retinal ganglia

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DESCRIPTION: (Applicant's Abstract) Retinal ganglion cells die in a variety of optic nerve diseases, the most prevalent of which is glaucoma. The mechanism of cell death is a genetically controlled program with 4 distinct stages. These stages are (i) early changes in gene expression that includes both the upregulation and downregulation of genes, (ii) the activation of key regulatory proteins such as p53 and BAX, (iii) dysfunction of mitochondria, and (iv) the activation of caspase proteases and nucleases. A goal in developing a neuroprotective strategy for ganglion cells is to block one or more of these stages of cell death. Current attempts to do this have shown that blocking late events (ii-iv) is not completely neuroprotective. As a consequence, we propose to characterize and block the early change in gene expression, specifically the downregulation. of genes in these cells. Preliminary studies indicate that ganglion cells exhibit extensive decreases in the expression of all normally active genes prior to the commitment to the cell death pathway. This includes genes that could enhance cell survival including Bc1X and the TrkB receptor genes. We will characterize further 3 classes of genes that may be affected by this silencing event and examine if histone deacetylation is the mechanism underlying the phenomenon. These latter experiments will be conducted by monitoring the acetylated status of histones on the ganglion cell marker gene Thy1, and by assessing the effects of inhibitors of histone deacetylases on Thy1 transcription and the activation of downstream events in the apoptotic program of ganglion cells.