Genetic Modulation of Glaucoma

青光眼的基因调控

• 批准号: 8023333
• 负责人: MONICA M JABLONSKI
• 金额: $ 37.38万
• 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/8023333
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Glaucoma is a highly prevalent group of diseases that, if uncontrolled, causes irreversible loss of vision. The underlying cause of the disease is not known in the majority of cases, therefore treatment options are limited to lowering the intraocular pressure. Outcomes of our proposed investigations will identify gene loci that modulate glaucoma severity to expand this sparse list of genes that are known to contribute to this disease.

描述（由申请人提供）：在此提案中，我们使用扩大的BXD重组近交菌株集来识别与调节青光眼严重程度有关的基因基因座。我们的方法结合了彻底的临床和实验室检查，以及对过去10年中产生的整个81种BXD线的微阵列分析，并明确研究了眼病和青光眼的遗传学。 BXD，DBA/2J的亲本菌株之一会发展为年龄相关的青光眼，此前是虹膜萎缩和色素分散体。虽然两个基因的突变等位基因TRYP1和GPNMB引起D2的虹膜疾病，但文献强烈表明这些突变不足以引起青光眼。具体而言，两个突变等位基因在C57BL/6J（BXD的另一个母体菌株）上渗入，导致对视神经损伤的明显抗性。这表明除引起色素色散的基因以外的基因会影响青光眼表型。当前的建议描述了定义修改基因座的独特机会。在AIM 1中，我们检验了以下假设：Tryp1和GPNMB中的合并突变不足以引起青光眼表型的各个方面。如果我们的假设是正确的，我们希望看到疾病的严重程度不仅取决于两个突变等位基因。我们已经确定了多个BXD菌株，其中IOP和遗传外交类型与无关。当我们系统地检查所有BXD菌株并在表型和外交型之间建立关系时，我们完全期望找到其他菌株，这些菌株无视对简单的两局疾病模型的期望。在AIM 2中，我们定义了调节青光眼严重程度的基因座和基因。为此，我们将识别和评估基因座中调节青光眼表型严重程度的候选基因。我们将对D2（2009年在UTHSC产生的大约50倍读取覆盖范围）以及大量的全眼和整个视网膜表达数据集中利用新的全基因组shot弹枪序列（约50倍的短读覆盖范围），我们也将其作为这项工作的序幕产生。我们期望使用最先进的生物信息学方法和常规分子测定有效地提名和评估候选青光眼基因。在AIM 3中，我们使用双向翻译。我们使用人类青光眼患者的同胞来测试AIM 2的小鼠候选者的翻译有效性。 J. Wiggs博士及其同事将使用在AIM 2中提名的候选青光眼基因进行重点基因关联研究。在相互反向翻译中，我们（MMJ和LL）将评估来自临床队列的已知，新和候选青光眼基因，并确定这些变体在BXDS中是否以及与青光眼相关的性状是否相关。结合了来自小鼠和人类青光眼研究的最高优先基因候选者，我们将生成易感性候选基因，连接表型和相关机制的分子和统计模型。 公共卫生相关性：青光眼是一群高度普遍的疾病，如果不受控制，会导致视力丧失。该疾病的根本原因在大多数情况下尚不清楚，因此治疗方案仅限于降低眼内压力。我们提出的研究的结果将确定调节青光眼严重程度的基因基因座，以扩大已知会导致该疾病的稀疏基因清单。