Complement activation in glaucoma

我们已经证明，在青光眼视网膜中表达改变的主要基因之一是： 补体成分C1 q。视网膜C1 q在DBA/2小鼠疾病过程的早期上调 青光眼模型。这一发现在青光眼领域被认为是非常重要的， 显示在激光诱导的猴青光眼以及人青光眼中发生类似的上调。在 此外，我们已经朝着产生同源C1 q敲除（KO）菌株的方向取得了重大进展， DBA/2背景，我们将在未来的研究中使用，以了解C1 q在青光眼中的作用。 C1 q和其他补体基因表达的变化表明， 该过程在视网膜神经节细胞（RGC）病理学中起作用。事实上，我们提出了初步的 证据表明炎症反应对于DBA/2小鼠中RGC损失的发展是至关重要的。 基于上述以及补体在调节适应性免疫中的作用，我们提出 以下关于补体激活如何参与青光眼发病机理的假设： 补体激活的中间成分导致RGC轴突和索马损伤，或者直接 或间接（通过对支持细胞、视网膜神经胶质、免疫细胞和细胞外基质的作用）。 为了验证这一假设，我们必须首先了解许多效应补体分子中的哪一种是 参与这个过程。因此，我们提出以下具体目标： 1. 测试预测，即中间补体组分的表达水平和/或量是 在诱导性和自发性（DBA/2）青光眼小鼠模型的视网膜中，以及在 激光诱导的灵长类动物青光眼和来自青光眼患者的人类样本。 2. 对我们之前产生的同类DBA/2 C1 q-/-动物进行表型表征 资助期，以确定是否通过经典途径补体激活参与 疾病的病理生理学 3. 产生同源DBA/2 C4 -/-和C3-/-动物，并在RGC和轴突生长方面对其进行表型分析。 损失以及胶质细胞活化，以确定C4和C3补体成分是否 这是恶性肿瘤病理学发展所必需的。 4. 通过比较C5在青光眼发病中的作用， 激光诱导的IOP升高的C5科斯和野生型小鼠中RGC损失和神经胶质活化。 本建议将剖析各种补充成分，以便准确确定 每一种都是青光眼的发病机制。这项工作的结果将对其他领域产生更广泛的影响。 神经退行性疾病

We have shown that one of the major genes with altered expression in the glaucomatous retina is complement component C1q. Retinal C1q is up-regulated early in the disease process in the DBA/2 mouse model of glaucoma. This finding has been recognized as very significant in the field of glaucoma as we have shown that a similar up-regulation occurs in laser induced monkey glaucoma as well as in human glaucoma. In addition we have made significant progress towards generating a congenic C1q knockout (KO) strain on the DBA/2 background which we will employ in future studies to understand the role of C1q in glaucoma. The changes in expression of C1q and other complement genes, suggest that a neuro-inflammatory process is operational in glaucomatous retinal ganglion cell (RGC) pathology. In fact we present preliminary evidence that an inflammatory reaction is critical for the development of RGC loss in the DBA/2 mouse. Based on the above and the role that complement plays in modulating adaptive immunity we propose the following hypothesis on how complement activation participates in the pathogenesis of glaucoma: Intermediate components of complement activation cause RGC axon and soma damage, either directly or indirectly (through effects on supportive cells, retinal glia, immune cells and extracellular matrix). To test this hypothesis we must first understand which of the many effector complement molecules is involved in this process. We thus propose the following specific aims: 1. Test the prediction that expression levels and/or amounts of intermediate complement components are altered in the retinas from induced and spontaneous (DBA/2) mouse models of glaucoma, as well as in laser induced primate glaucoma and human specimens from patients with glaucoma. 2. Characterize phenotypically the congenic DBA/2 C1q -/- animals we have generated in the previous funding period to determine whether complement activation through the classical pathway is involved in the pathophysiology of the disease. 3. Generate congenic DBA/2 C4 -/- and C3-/- animals and phenotype them in respect to RGC and axonal loss as well as glial activation to determine whether the C4 and C3 complement components are required for development of the glaucomatous pathology. 4. Determine whether C5 has a protective role in the pathogenesis of glaucoma by comparing the amount of RGC loss and glial activation in C5 KOs and wild type mice subjected to laser-induced IOP elevation. This proposal will dissect the various complement components to allow precise determination of the role of each one in the pathogenesis of glaucoma. Findings from this work will have wider implications for other neurodegenerative disease.