Prevention of macular pathophysiology associated with F3 misfolding

摘要 老年性黄斑变性(AMD)是导致人类不可逆性失明的主要原因 工业化国家中年龄超过60岁的人。在世界范围内，据估计，近 到2040年，将有3亿人患有某种形式的AMD。到目前为止，还没有有效的治疗方法。 用于阻止干性AMD进展，这种形式影响90%的AMD患者。唯一的 减缓这种形式的AMD的建议是服用高剂量的维生素和矿物质补充剂 每天。新的证据表明，纤维蛋白-3(F3)的突变或改变，一种分泌的 功能未知的蛋白质，在影响黄斑发病机制中起着突出作用 退行性疾病。一个具体的例子是F3中的R345W突变如何导致早期 首发的黄斑营养不良症称为马拉蒂亚氏病(ML)，其特征是 补体激活、炎性细胞因子的产生以及视网膜下色素 上皮细胞(RPE)沉积。然而，总的来说，人们缺乏关于如何 这些黄斑变性会发展成。此外，对这两种疾病都没有有效的治疗方法。 ML或更流行的疾病，干性AMD。因此，迫切需要开发一种 对类似AMD疾病的根本原因的机械性理解，如ML，以及 为他们找出新的治疗方法。在这项提案中，我们计划：i)测试针对 防止RPE细胞分泌错误折叠的R345W F3，II)使用一种新的、有条件的 调控R345W F3错误折叠下游炎症信号的方法，以及III)试验 WT F3是否也是次RPE矿床形成所必需的。在研究结束时，我们 希望更好地了解错误折叠的F3-促进的分子基础 炎症和亚RPE蛋白沉积，并确定一些治疗- 治疗多发性骨髓瘤的简便方法。我们获得的关于F3折叠错误的洞察力 与引发炎症和亚RPE沉积有关的因素可能更广泛地应用于 常见的视网膜疾病，如干性黄斑变性。

ABSTRACT Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people greater than 60 years of age in industrialized countries. Worldwide, it is estimated that nearly 300 million people will have some form of AMD by 2040. Thus far, no effective treatment exists for halting dry AMD progression, the form which affects 90% of all AMD patients. The only suggestion for slowing this form of AMD is to take high-dose vitamin and mineral supplements daily. Emerging evidence suggests that mutations or alterations in fibulin-3 (F3), a secreted protein of unknown function, plays a prominent role in influencing the pathogenesis of macular degenerative diseases. One specific example is how an R345W mutation in F3 causes an early onset macular dystrophy called Malattia Leventinese (ML), which is characterized by complement activation, production of inflammatory cytokines, as well as sub-retinal pigment epithelium (RPE) deposits. However, in general, there is a lack of knowledge regarding how these macular degenerations develop. Furthermore, there are no effective treatments for either ML or the more prevalent disease, dry AMD. Therefore, there is an urgent need to develop a mechanistic understanding of the underlying causes of AMD-like diseases, such as ML, and to identify new therapies for them. In this proposal we plan to i) test genetic strategies directed at preventing the secretion of misfolded R345W F3 from RPE cells, ii) employ a novel, conditional approach to regulate inflammatory signaling downstream of R345W F3 misfolding, and iii) test whether WT F3 is also necessary for sub-RPE deposit formation. At the end of the study, we hope to have a better understanding of the molecular basis by which misfolded F3-facilitates inflammation and sub-RPE protein deposition, and to identify a number of therapeutically- tractable approaches for treating ML. The insight that we gain regarding how misfolded F3 is involved in triggering inflammation and sub-RPE deposits can likely be applied more broadly to prevalent retinal diseases such as dry AMD.