LOXL1 and Pseudoexfoliation Glaucoma: Studies in Animal Models

LOXL1 和假性剥脱性青光眼：动物模型研究

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：最近的人类遗传研究表明，LOXL1（类似1）变体与假脱糖效果青光眼密切相关。这些发现与较旧的文献一致，表明假脱糖纤维瘤与弹性纤维维持的缺陷有关，因为我们已经表明loxl1在弹性纤维稳态中起关键作用。最新的数据将LOXL1变体与假脱糖曲线青光眼相结合，以及我们对LOXL1依赖性弹性纤维稳态的长期兴趣为这项探索性研究提供了基础。提出了两个相互关联的特定目标。首先，我们将确定LOXL1功能/表达的扰动是否导致动物模型中的眼部表型，这与伪脱糖青光眼的临床特征一致。我们将研究我们现有的LOXL1 NULL突变模型和通过体细胞基因转移产生的其他模型。其次，我们旨在获得机械洞察力，了解LOLX1功能的扰动如何导致伪脱糖性青光眼。除了测定青光眼变化外，还将对眼组织中的弹性纤维系统及其代谢产物进行分析。鉴于伪脱糖条件的复杂遗传，可能会影响疾病的发展。因此，也将探索LOXL1与次要因素相互作用以创建完整临床疾病的可能性。伪脱糖性青光眼是公共卫生相关性疾病机制，这是一种相对常见的青光眼形式，尚不清楚。拟议的研究将尝试使用动物模型在LOLX1中的缺陷与假脱糖效果的缺陷之间建立因果关系。我们预计该项目将对这种情况的致病机制产生新的见解，并提出疾病筛查和治疗干预的可能策略。