LOXL1 and Pseudoexfoliation Glaucoma: Studies in Animal Models

LOXL1 和假性剥脱性青光眼：动物模型研究

• 批准号: 7685375
• 负责人: Janey L Wiggs
• 金额: $ 18.88万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7685375
• 关键词: Affect; Animal Model; Anterior; Aqueous Humor; Biological; Biological Assay; Blood-Aqueous Barrier; Bruch' s basal membrane structure; Catalytic Domain; Clinic; Clinical; Complex; Data; Defect; Deposition; Development; Disease; Ear; Elastic Fiber; Elastin; Environmental Risk Factor; Enzymes; Etiology; Exfoliation Syndrome; Extracellular Matrix; Extravasation; Eye; Family; Genes; Genetic; Genetic Variation; Glaucoma; Homeostasis; Human Genetics; Individual; Iris; Knockout Mice; LOX gene; Lead; Link; Liquid substance; Literature; Maintenance; Manuscripts; Massachusetts; Mediating; Modeling; Molecular; Mus; N-terminal; Open-Angle Glaucoma; Other Genetics; Pathogenesis; Pathway interactions; Peptides; Phenotype; Physiologic Intraocular Pressure; Play; Polymers; Process; Property; Protein-Lysine 6-Oxidase; Regulation; Research Personnel; Risk Factors; Role; Sampling; Screening procedure; Serum Proteins; Simulate; Somatic Gene Therapy; Structure of sinus venosus of sclera; Surface; System; Testing; Therapeutic Intervention; Time; Tissues; Trabecular meshwork structure; Variant; age related; aqueous; base; crosslink; cytokine; gain of function; genome wide association study; insight; interest; link protein; member; mutant; population based; public health relevance; research study; scaffold; theories

DESCRIPTION (provided by applicant): Recent human genetic studies show that LOXL1 (lysyl oxidase like 1) variants are strongly associated with pseudoexfoliation glaucoma. These findings are consistent with older literature suggesting that pseudoexfoliation glaucoma is associated with a defect in elastic fiber maintenance, since we have shown that LOXL1 plays a key role in elastic fiber homeostasis. The recent data connecting LOXL1 variants with pseudoexfoliation glaucoma combined with our long-standing interest in LOXL1-dependent elastic fiber homeostasis provides the basis for this exploratory study. Two inter-related specific aims are being proposed. First we will determine if perturbation of LOXL1 function/expression results in an ocular phenotype in the animal model consistent with the clinical features of pseudoexfoliation glaucoma. We will study our existing LOXL1 null mutant model and additional models generated through somatic gene transfer. Second, we aim to gain mechanistic insight into how the perturbation of LOLX1 function leads to pseudoexfoliation glaucoma. Analysis of the elastic fiber system in ocular tissues and its metabolites will be carried out, in addition to assays for glaucomatous changes. Given the complex inheritance of the pseudoexfoliation condition, it is likely that additional genetic and/or environmental factors could influence the development of the disease. Therefore the possibility that LOXL1 may interact with secondary factors to create the full clinical disease will also be explored. PUBLIC HEALTH RELEVANCE Disease mechanism underlying pseudoexfoliation glaucoma, a relatively common form of glaucoma, is not well understood. The proposed studies will attempt to establish a causal link between a defect in LOLX1 and pseudoexfoliation glaucoma using animal models. We expect the project to yield new insights into the pathogenic mechanism of this condition, and suggest possible strategies for disease screening and therapeutic intervention.

描述（由申请人提供）：最近的人类遗传学研究表明，LOXL 1（赖氨酰氧化酶样1）变体与假性剥脱性青光眼密切相关。这些发现与较早的文献一致，表明假性剥脱性青光眼与弹性纤维维持缺陷相关，因为我们已经表明LOXL 1在弹性纤维稳态中起关键作用。最近的数据连接LOXL 1变异与假性剥脱性青光眼结合我们长期的兴趣LOXL 1依赖性弹性纤维稳态提供了基础，这项探索性研究。提出了两个相互关联的具体目标。首先，我们将确定LOXL 1功能/表达的扰动是否导致与假性剥脱性青光眼的临床特征一致的动物模型中的眼部表型。我们将研究我们现有的LOXL 1无效突变模型和通过体细胞基因转移产生的其他模型。其次，我们的目标是获得机制的见解LOLX 1功能的扰动如何导致假性剥脱性青光眼。除了对青光眼变化的测定外，还将对眼组织中的弹性纤维系统及其代谢物进行分析。鉴于假性剥脱症的复杂遗传，可能有其他遗传和/或环境因素可能影响疾病的发展。因此，还将探索LOXL 1可能与次要因素相互作用以产生完整临床疾病的可能性。假性剥脱性青光眼是一种相对常见的青光眼，其潜在的疾病机制尚不清楚。拟议的研究将尝试使用动物模型建立LOLX 1缺陷和假性剥脱性青光眼之间的因果关系。我们希望该项目能够对这种疾病的致病机制产生新的见解，并为疾病筛查和治疗干预提出可能的策略。