Retina Differential Gene Expression Modifiers that affect Vision

影响视力的视网膜差异基因表达修饰剂

• 批准号: 10001521
• 负责人: Salma Ferdous
• 金额: $ 3.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-04-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001521
• 关键词: ARHGEF5 gene; Adult; Affect; Amino Acids; Bacterial Artificial Chromosomes; Blindness; Candidate Disease Gene; Cells; Chromosome 4; Data Set; Defect; Development; Disease; Emotional; Ensure; Epigenetic Process; Excision; Exhibits; Exons; Family; Future; Generations; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Goals; Health; Histone Code; Inbred Strains Mice; Inbreeding; Individual; Inheritance Patterns; Inherited; KDM1A gene; Knockout Mice; Maps; Messenger RNA; Metabolic; Methylation; Microarray Analysis; Molecular; Mouse Strains; Mus; Mutation; Onset of illness; Organism; Outcome; Oxygen; Partner in relationship; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Photoreceptors; Plasmids; Population; Protein Biosynthesis; Proteins; Proteome; Quantitative Trait Loci; RNA; RNA Processing; RNA Splicing; Recombinants; Regulation; Retina; Retinal Diseases; Retinitis; Retinitis Pigmentosa; Role; Severities; Siblings; Symptoms; System; Testing; Tissue-Specific Gene Expression; Tissues; Transcript; Variant; Vertebrate Photoreceptors; Vision; Visual; aged; causal variant; cell type; chromatin immunoprecipitation; clinical heterogeneity; conditional knockout; differential expression; disease-causing mutation; effective therapy; genetic corepressor; histone methylation; mRNA Expression; mRNA Precursor; methylation pattern; next generation sequencing; prevent; protein expression; small molecular inhibitor; socioeconomics; therapy development; trait; transcriptome; treatment strategy; whole genome; young adult

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.

项目概要： 遗传性视网膜疾病（IRD）是成年工作人群失明的主要原因， 给患者及其家庭带来巨大的情感和社会经济负担。近200个基因的突变 已被证明会导致IRD，然而，目前没有治疗方案可用于预防疾病 发病，增加视觉功能，或延迟视力丧失。发展有效的 治疗策略是这些疾病临床表现的异质性。这种表型变异 呈现可能是由于个体之间的遗传变异，甚至是同一家族内的个体。一 对这种变异的可能解释是与致病基因相互作用的遗传修饰剂。遗传 在许多疾病中已经发现了修饰剂并且可以影响许多方面包括疾病发作， 严重程度和进展。许多IRD引起的突变影响参与RNA加工的基因， 由于特殊视网膜细胞类型（如光感受器）的高代谢需求， 对异常的RNA加工敏感我们的实验室已经暗示了小鼠4号染色体上的0.3Mb区域， 在55个重组体中，它控制着基因组中约170个外显子的差异表达。 近交系小鼠外显子在亲本菌株C57 BL/6 J和C57 BL/6 J中具有二分表达模式。 DBA/2 J，其中特定外显子在C57 BL/6 J中具有相对高的表达，而在C57 BL/6 J中具有相对低的表达。 DBA/2J。这个建议的前提是确定位于这0.3Mb区域的基因，控制这一点。 孟德尔式遗传模式表型。Lsd 1是在0.3Mb位点发现的六个基因之一， 在C57 BL/6 J和DBA/2 J之间有四个非同义的变化。该基因座中的其他四个基因 缺少任何非同义的变化并且是低优先级的。Lsd 1是我们最优先考虑的候选对象，因为它具有以下功能： 视杆和视锥的终末分化。我们假设Lsd 1，一种已知的表观遗传调节因子， 在发育中的视网膜中的转录辅抑制因子，控制这种差异外显子表达，是一种遗传调节因子。 IRD的修改器。我们将通过以下方法确定Lsd 1是否控制成年小鼠的差异表达： 对Lsd 1条件性基因敲除小鼠和转基因Lsd 1经典基因敲除小鼠进行基因芯片分析。 此外，我们还将评估C57 BL/6 J和DBA/2 J之间的组蛋白编码差异是否是导致C57 BL/6 J和DBA/2 J之间组蛋白编码差异的原因。 成人视网膜中差异表达的潜在机制。