Impact of Mutant IL-20RB on Glaucoma

突变体 IL-20RB 对青光眼的影响

• 批准号: 9340230
• 负责人: Mary K Wirtz
• 金额: $ 15.98万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340230
• 关键词: Address; Affect; African; Anterior; Antibodies; Appearance; Aqueous Humor; Binding; Binding Sites; Biological; Biological Models; Biological Process; Blindness; Cells; Characteristics; Chronic; Complex; Data; Diagnosis; Disease; Economic Burden; Etiology; Event; Eye; Family; Fibroblasts; Genes; Glaucoma; Grant; Heterodimerization; Human; Individual; Lead; Measures; Mechanics; Methods; Mutation; Optic Disk; Oregon; Patients; Peripheral; Physiologic Intraocular Pressure; Play; Primary Open Angle Glaucoma; Proteins; Regulation; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stress; Stretching; Surface Plasmon Resonance; TYRP1 gene; Time; Tissues; Trabecular meshwork structure; United States; Vision; Visual Fields; Work; aging population; aqueous; base; cell type; clinical Diagnosis; cytokine; effective therapy; genetic pedigree; genetic variant; high intraocular pressure; improved; insight; interleukin 20; interleukin-19; mutant; optic nerve disorder; pressure; protein B; receptor; receptor binding; receptor function; response

PROJECT SUMMARY Glaucoma is a debilitating disease, resulting in loss of peripheral vision and eventual total blindness if not treated adequately. Primary open angle glaucoma (POAG) is the most common form of glaucoma in Western and African nations. While the exact etiology of POAG remains unknown, it is clearly a group of heterogeneous disorders frequently associated with elevated intraocular pressure. Pedigree studies utilizing large POAG families are a powerful method to identify rare genetic variants that predispose individuals to glaucoma. By focusing on one family, the complexity of this disease can be reduced to a simpler form that is more likely to have one causal event. In a large POAG family we recently identified a mutation in interleukin- 20 receptor B (IL-20RB), which is predicted to impact binding of the receptor to the IL-20 family of cytokines. All affected patients in this family have high intraocular pressures (>22mm Hg). Our hypothesis is that the IL-20 signaling pathway functions to regulate aqueous outflow and the T104M mutation in IL-20RB results in defective propagation of signals in POAG patients. The aim of this grant is to gain a better understanding of how a mutation in a critical site in IL- 20RB leads to elevated intraocular pressure and ultimately to glaucoma. The trabecular meshwork is the tissue in the anterior of the eye that functions to regulate intraocular pressure. IL-20 signaling in trabecular meshwork cells will be investigated using two model systems - perfused anterior segments and mechanical stretch of trabecular meshwork cells. Binding of the IL-20 cytokine subfamily to the IL-20 type I and type II heterodimeric receptors containing the mutant T104M IL-20RB protein will be analyzed using plasmon resonance. We will determine the downstream effect of defective signaling through the mutant IL-20RB receptor using mechanical stretch of patient mutant and wild-type fibroblasts. The proposed work has great potential for leading to new insights into the function of the IL-20 family of signaling molecules in regulating aqueous outflow and intraocular pressure. This is the first step to developing improved therapy for this blinding disease.

项目摘要 青光眼是一种使人衰弱的疾病，导致周边视力丧失，最终导致全 如果治疗不当，会导致失明。原发性开角型青光眼（POAG）是最常见的 西方和非洲国家的一种青光眼。虽然原发性开角型青光眼的确切病因仍然是 未知，它显然是一组异质性疾病，经常与升高的 眼压利用大的POAG家族进行家系研究是一种强有力的方法， 鉴定使个体易患青光眼的罕见遗传变异。通过专注于一个 家庭，这种疾病的复杂性可以减少到一个更简单的形式，更有可能 有一个因果事件。在一个大的POAG家族中，我们最近发现了白细胞介素的突变- IL-20受体B（IL-20 RB），其被预测影响受体与IL-20家族的结合 细胞因子。该家族中所有受影响的患者都有高眼内压（> 22 mm Hg）。 我们的假设是IL-20信号通路的功能是调节房水流出， IL-20 RB中的T104 M突变导致POAG患者中信号传播缺陷。 这项资助的目的是更好地了解IL-10基因关键位点的突变是如何发生的， 20 RB导致眼内压升高，最终导致青光眼。小梁 网状结构是眼睛前部的组织，其功能是调节眼内压。 将使用两种模型系统研究小梁网细胞中的IL-20信号传导： 灌注眼前节和机械牵张小梁网细胞。结合 IL-20 I型和II型异二聚体受体的IL-20细胞因子亚家族， 使用等离子体共振分析突变T104 M IL-20 RB蛋白。我们将 确定通过突变型IL-20 RB受体的缺陷信号传导的下游效应 使用患者突变体和野生型成纤维细胞的机械拉伸。拟议的工作有 对IL-20信号家族功能的新见解具有巨大潜力 分子调节房水流出和眼内压。这是第一步， 为这种致盲性疾病开发更好的治疗方法