Impact of Mutant IL-20RB on Glaucoma

项目总结 青光眼是一种使人衰弱的疾病，会导致周边视力丧失，最终导致整体视力下降。 如果得不到适当的治疗，就会失明。原发性开角型青光眼(POAG)最常见 在西方和非洲国家青光眼的一种形式。虽然POAG的确切病因仍然存在 未知，显然是一组异质性疾病，经常与升高有关 眼压。利用POAG大家系进行系谱研究是一种强有力的方法 找出易患青光眼的罕见基因变异。通过专注于一个 这种疾病的复杂性可以简化为一种更简单的形式，更有可能是 有一个因果事件。在一个POAG大家庭中，我们最近发现了白细胞介素1的突变。 20受体B(IL-20RB)，预计会影响受体与IL-20家族的结合 细胞因子。这个家族中所有受影响的患者都有高眼压(&gt；22 mm Hg)。 我们的假设是，IL-20信号通路起调节房水流出和 IL-20Rb基因T104M突变导致POAG患者信号传播障碍。 这项拨款的目的是为了更好地了解IL-1中一个关键部位的突变是如何- 20RB会导致眼压升高，最终导致青光眼。骨小梁 眼网是位于眼球前部的组织，其功能是调节眼压。 小梁细胞中的IL-20信号将使用两个模型系统进行研究- 小梁细胞前段灌流和机械拉伸。约束： IL-20I型和II型异二聚体受体的IL-20细胞因子亚家族包括 突变的T104M IL-20RB蛋白将用等离子共振进行分析。我们会 通过突变型IL-20RB受体确定缺陷信号的下游效应 使用机械拉伸的患者突变和野生型成纤维细胞。拟议的工作包括 引导对IL-20信号家族功能的新见解的巨大潜力 调节房水流出和眼压的分子。这是迈向 为这种致盲疾病开发改进的治疗方法。

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.