Genetic Modulation of Glaucoma

青光眼的基因调控

• 批准号: 8269646
• 负责人: MONICA M JABLONSKI
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269646
• 关键词: Alleles; Atrophic; Bioinformatics; Biological Assay; Blindness; Candidate Disease Gene; Cell Count; Clinical; Data; Data Set; Disease; Disease model; Evaluation; Eye; Eye diseases; Genes; Genetic; Genotype; Glaucoma; Haplotypes; Human; Human Chromosomes; Investigation; Iris; Iris Diseases; Laboratories; Lead; Link; Literature; Maps; Methods; Microarray Analysis; Molecular; Molecular Models; Mus; Mutation; Open-Angle Glaucoma; Optic Nerve; Outcome; Parents; Patients; Penetrance; Phenotype; Physiologic Intraocular Pressure; Pigments; Predisposition; Quantitative Trait Loci; Reading; Recombinant Inbred Strain; Research; Research Personnel; Resistance; Retina; Severities; Severity of illness; Statistical Models; Surveys; Testing; Translations; Variant; Whole-Genome Shotgun Sequencing; Work; age related; authority; cohort; expectation; experience; ganglion cell; molecular modeling; mutant; trait

In this proposal, we use our enlarged set of BXD recombinant inbred strains to identify gene loci that are involved in modulating the severity of glaucoma. Our approach combines a thorough clinical and laboratory examination, and microarray analysis of the entire set of 81 BXD lines generated over the last 10 years with the express purpose of studying the genetics of eye disease and glaucoma. One of the parental strains of BXD, DBA/2J, develop an age-related glaucoma that is preceded by iris atrophy and pigment dispersion. While mutant alleles of two genes, Tryp1 and Gpnmb, cause the iris disease in D2, the literature strongly suggests that these mutations are not sufficient to cause glaucoma. Specifically, introgression of both mutant alleles onto C57BL/6J, the other parent strain of BXD, results in a marked resistance to optic nerve damage. This indicates that genes other than those that cause pigment dispersion influence the glaucomatous phenotype. The current proposal describes a unique opportunity to define the modifying loci. In Aim 1, we test the hypothesis that the combined mutations in Tryp1 and Gpnmb are not sufficient to cause all aspects of the glaucoma phenotype. If our hypothesis is true, we expect to see that the severity of disease is not solely dependent on the two mutant alleles. We have already identified multiple BXD strains in which IOP and genetic diplotype are not correlated. As we systematically examine all BXD strains and establish relations between phenotype and diplotype, we fully expect to find additional strains that defy expectations of a simple two-locus disease model. In Aim 2, we define loci and genes that modulate glaucoma severity. To do so, we will identify and evaluate candidate genes within loci that modulate the severity of the glaucoma phenotype. We will exploit our new whole genome shotgun sequence for D2 (about >50x short read coverage generated at UTHSC in 2009) along with massive whole eye and whole retina expression datasets that we have also generated as a prelude to this work. We expect to efficiently nominate and evaluate candidate glaucoma genes using state-of-the-art bioinformatic methods and conventional molecular assays. In Aim 3, we use bidirectional translation. We test the translational validity of mouse candidates from Aim 2 using cohorts of human glaucoma patients. Dr. J. Wiggs and colleagues will perform focused gene association studies using candidate glaucoma genes nominated in Aim 2. Specifically, we use association analyses of markers encompassing syntenic regions of human chromosomes. In reciprocal reverse translation, we (MMJ and LL) will evaluate known, new, and candidate glaucoma genes from clinical cohorts and determine if and how these variants are associated with glaucoma- associated traits in BXDs. Combining the top priority gene candidates from both mouse and human glaucoma studies, we will generate molecular and statistical models of susceptibility candidate genes, linked phenotypes, and associated mechanisms.

在这个建议中，我们使用我们的扩大的BXD重组自交系来鉴定基因位点