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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：遗传性视网膜疾病（IRD）是成年人群失明的主要原因，并提出对患者及其家人的巨大情感和社会经济负担。近200个基因的突变但是已显示引起IRD，但是目前尚无治疗选择来预防疾病发作，增加视觉功能或延迟视力丧失。开发有效的一个主要挑战治疗策略是这些疾病中临床表现的异质性。这种表型变化呈现可能是由于个体之间，甚至同一家族中的遗传变异所致。一变异的可能解释是与疾病基因相互作用的遗传修饰剂。遗传在许多疾病中发现了修饰剂，可以影响许多方面，包括疾病发作，严重性和进展。许多引起IRD的突变会影响参与RNA处理的基因，并且由于特殊视网膜细胞类型的高代谢需求，例如感光器，视网膜特别是对异常RNA处理敏感。我们的实验室已牵涉到小鼠染色体上的0.3MB区域，控制位于整个基因组的基因中〜170外显子的差异表达，55个重组近交小鼠菌株。外显子在父母菌株中具有二分法表达模式，C57BL/6J和 DBA/2J，特定的外显子在C57BL/6J中具有相对较高的表达，并且在 DBA/2J。该提案的前提是确定控制此局的0.3MB区域中的基因孟德尔式的遗传模式表型。 LSD1是在0.3 MB基因座中发现的六个基因之一，它是展示C57BL/6J和DBA/2J之间的四个非同义变化。基因座中的其他四个基因缺乏任何非同义变化，优先级较低。 LSD1是我们的首要候选人，因为它具有功能杆和锥的末端分化。我们假设LSD1是一种已知的表观遗传调节剂和发育中的视网膜中的转录核压子，控制这种差异外显子的表达，是一种遗传 IRD的修饰符。我们将通过对LSD1进行微阵列分析，有条件敲除小鼠和转基因LSD1经典基因敲除小鼠。此外，我们将评估C57BL/6J和DBA/2J之间的组蛋白代码差异是成人视网膜差异表达的基础机制。