The Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA.
J Clin Invest. 2011 Apr;121(4):1429-44. doi: 10.1172/JCI44646. Epub 2011 Mar 7.
Glaucoma is one of the most common neurodegenerative diseases. Despite this, the earliest stages of this complex disease are still unclear. This study was specifically designed to identify early stages of glaucoma in DBA/2J mice. To do this, we used genome-wide expression profiling of optic nerve head and retina and a series of computational methods. Eyes with no detectable glaucoma by conventional assays were grouped into molecularly defined stages of disease using unbiased hierarchical clustering. These stages represent a temporally ordered sequence of glaucoma states. We then determined networks and biological processes that were altered at these early stages. Early-stage expression changes included upregulation of both the complement cascade and the endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in complement component 1a (C1qa) were protected from glaucoma. Similarly, inhibition of the endothelin system with bosentan, an endothelin receptor antagonist, was strongly protective against glaucomatous damage. Since endothelin 2 is potently vasoconstrictive and was produced by microglia/macrophages, our data provide what we believe to be a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early molecular events, such as complement and endothelin induction, may provide effective new treatments for human glaucoma.
青光眼是最常见的神经退行性疾病之一。尽管如此，这种复杂疾病的早期阶段仍不清楚。本研究专门旨在确定 DBA/2J 小鼠青光眼的早期阶段。为此，我们使用视神经头部和视网膜的全基因组表达谱分析以及一系列计算方法。通过常规检测未检测到青光眼的眼睛使用无偏分级聚类被分为分子定义的疾病阶段。这些阶段代表了青光眼状态的时间有序序列。然后，我们确定了在这些早期阶段发生改变的网络和生物学过程。早期阶段的表达变化包括补体级联和内皮素系统的上调，因此我们测试了分别抑制它们的治疗价值。补体成分 1a（C1qa）突变的小鼠免受青光眼的侵害。同样，内皮素受体拮抗剂博来霉素抑制内皮素系统对青光眼损伤有很强的保护作用。由于内皮素 2 具有强烈的血管收缩作用并且由小胶质细胞/巨噬细胞产生，我们的数据提供了我们认为在这些细胞类型和青光眼血管功能障碍之间存在新的联系。针对补体和内皮素诱导等早期分子事件可能为人类青光眼提供有效的新治疗方法。
