Retina Differential Gene Expression Modifiers that affect Vision

项目总结： 遗传性视网膜疾病(IRD)是成年工作人群失明的一个主要原因，并呈现出一种 给患者及其家人带来巨大的情感和社会经济负担。近200个基因的突变 已经被证明会导致红斑狼疮，然而，目前还没有可用的治疗方案来预防疾病 发病、增加视觉功能或延缓视力丧失。有效发展的一个主要挑战 治疗策略是这些疾病临床表现的异质性。这种表型变异在 表现可能是由于个体之间的遗传差异，甚至是同一个家庭中的那些人。一 这种变异的可能解释是与致病基因相互作用的遗传修饰物。遗传 修饰物已经在许多疾病中被发现，并可以影响许多方面，包括疾病的发生， 严重性和进展性。许多导致IRD的突变会影响参与RNA加工的基因，并由于 对于特殊的视网膜细胞类型的高代谢需求，如光感受器，视网膜尤其 对异常的RNA加工敏感。我们的实验室在小鼠4号染色体上发现了一个0.3Mb的区域 控制~170外显子在55个重组人基因组中的差异表达 近交系小鼠品系。外显子在亲本菌株C57BL/6J和C57BL/6J中的表达模式为二分。 DBA/2J，其中一个外显子在C57BL/6J中高表达，在C57BL/6J中低表达 DBA/2J。这一建议的前提是确定位于这0.3Mb区域的控制这一基因 孟德尔式遗传模式表型。LSD1是在0.3Mb基因座上发现的六个基因之一，它 显示了C57BL/6J和DBA/2J之间的四个非同义变化。该基因座上的其他四个基因 缺少任何非同义词的更改，优先级较低。LSD1是我们的首选方案，因为它在 杆状和圆锥体的末端分化。我们假设LSD1，一个已知的表观遗传调节因子和 在发育中的视网膜中的转录抑制因子，控制着这个差异外显子的表达，是一种基因 IRDS的修饰符。我们将通过以下方式确定LSD1是否控制成年小鼠的差异表达 对LSD1条件性基因敲除小鼠和转基因LSD1经典基因敲除小鼠进行基因芯片分析。 此外，我们将评估C57BL/6J和DBA/2J之间的组蛋白编码差异是否是 成人视网膜差异表达的机制。

Project Summary: Inherited retinal diseases (IRDs) are a major cause of blindness in the working adult population and present an enormous emotional and socioeconomic burden on patients and their families. Mutations in almost 200 genes have been shown to cause IRDs, however, no treatment options are currently available to prevent disease onset, increase visual function, or delay vision loss. One major challenge in the development of effective treatment strategies is the heterogeneity of clinical presentation in these diseases. This phenotypic variation in presentation is likely due to genetic variation between individuals, even those within the same family. One possible explanation for the variation are genetic modifiers that interact with the disease-causing gene. Genetic modifiers have been discovered in many diseases and can influence many aspects including disease onset, severity, and progression. Many IRD-causing mutations affect genes involved in RNA processing and due to the high metabolic needs of specialized retinal cell types, such as photoreceptors, the retina is particularly sensitive to aberrant RNA processing. Our lab has implicated a 0.3Mb region on mouse chromosome 4 that controls the differential expression of ~170 exons in genes located throughout the genome in 55 recombinant inbred mouse strains. The exons have a dichotomous expression pattern in the parental strains, C57BL/6J and DBA/2J, with a particular exon having relatively high expression in C57BL/6J and relatively low expression in DBA/2J. The premise of this proposal is to identify the gene located in this 0.3Mb region that controls this Mendelian-like inheritance pattern phenotype. Lsd1 is one of six genes found in the 0.3 Mb locus, and it exhibits four nonsynonymous changes between C57BL/6J and DBA/2J. Four of the other genes in the locus lack any nonsynonymous changes and are low priority. Lsd1 is our top priority candidate as it has functions in the terminal differentiation of rods and cones. We hypothesize that Lsd1, a known epigenetic regulator and transcriptional corepressor in the developing retina, controls this differential exon expression and is a genetic modifier of IRDs. We will determine whether Lsd1 is controlling differential expression in adult mice by performing microarray analysis on Lsd1 conditional knock out mice andtransgenic Lsd1 classic knockout mice. Additionally, we will assess whether histone code differences between C57BL/6J and DBA/2J are the mechanism underlying the differential expression in adult retina.