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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.

项目总结: