Transcriptional silencing in damaged retinal ganglia

描述：(申请人摘要)视网膜神经节细胞在多种疾病中死亡 视神经疾病，其中最常见的是青光眼。它的作用机制 细胞死亡是一个由基因控制的程序，有4个不同的阶段。这些 阶段是(I)基因表达的早期变化，包括 基因的上调和下调，(Ii)关键调控的激活 P53和Bax等蛋白质，(Iii)线粒体功能障碍，以及(Iv) 激活半胱氨酸天冬氨酸蛋白酶和核酸酶。开发一种 神经节细胞的神经保护策略是阻断其中的一个或多个 细胞死亡的各个阶段。目前这样做的尝试表明，阻止延迟 事件(II-IV)并不完全具有神经保护作用。因此，我们建议 以确定和阻止基因表达的早期变化，特别是下调。这些细胞中的基因。初步研究表明， 正常情况下，神经节细胞中ALL的表达广泛减少 在承诺进入细胞死亡途径之前的活跃基因。这包括 可以提高细胞存活率的基因包括Bc1X和TrkB受体 基因。我们将进一步描述可能受影响的3类基因 这一沉默事件和检验组蛋白去乙酰化是否是机制 这一现象背后的原因。后一项实验将由 监测组蛋白在神经节细胞标志基因上的乙酰化状态 Thy1，并通过评估组蛋白脱乙酰酶抑制剂对 Thy1转录与细胞凋亡中下游事件的激活 神经节细胞的程序。

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.