Complement Factor H Haplotypes and Smoking in Age-Related Macular Degeneration

描述（由申请人提供）： 视网膜相关性黄斑变性（AMD）是一种涉及遗传因素和环境损伤的缓慢进展的多因素疾病。AMD是导致60岁以上美国人失明的主要原因。随着人口老龄化，AMD的患病率将继续增长，在75岁时达到约30%的最大风险率。由于吸烟显著增加了AMD的风险，并且退伍军人中吸烟的发生率比一般美国成年平民高20%，因此VA系统将不得不为可能高达700万或更多的AMD病例提供护理。目前可用的治疗集中在疾病的晚期（脉络膜新生血管; CNV）;然而，这些治疗具有显著的风险，并且仅针对AMD患者的亚群。对于早期AMD没有可用的治疗（i>所有病例的85%）。因此，至关重要的是，我们要学会如何早期检测AMD，并开发早期疾病预防的治疗方法。虽然机理研究已经表明炎症和吸烟是两种形式的AMD的基本组成部分，但遗传研究已经证明，不同补体蛋白中的多态性各自增加了发展AMD的风险。最有害的突变之一发生在补体级联反应中的一种重要的调节因子H（fH）（fH风险单倍型）。总体而言，已经假设补体驱动的炎症控制不足可能是AMD疾病发病机制的主要因素。在这里，我们希望回答两个基本问题：1）吸烟和补体在疾病过程中是否协同作用; 2）我们能否在吸烟相关病理学中靶向补体级联反应进行治疗。对于该提议，我们将以我们的总体假设为指导，即AP的病理性激活对RPE具有直接影响，从而为AMD病理产生容许的细胞环境。目的1旨在确定烟雾诱导的RPE单层补体激活途径。在目标2中，我们将测试检查受试者血清中的补体水平，将水平与单倍型和疾病相关联。最后，我们的假设将在目标3中进行体内测试。我们将使用补体抑制策略，使用靶向抑制剂阻断替代补体级联反应，以干扰CNV和吸烟诱导的病理学。测试旁路途径抑制剂不仅将确立其治疗价值，而且另外，阐明其在动物模型中的机制将研究补体旁路途径在AMD病理学中的作用和贡献。综上所述，当前Merit审查提案的目的是进一步表征补体激活和吸烟之间的相互作用;而长期目标是开发一种新的治疗方法，以减少AMD病例数量，改善退伍军人护理和生活质量。在成功完成本文所述的实验后，我们希望在较大的AMD动物模型中开始后续研究，探索化合物的药代动力学和毒理学，以最终准备进行人体临床试验。

DESCRIPTION (provided by applicant): Project Summary Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic ab- normalities and environmental insults. AMD is the leading cause of blindness for Americans over age sixty. As the population ages, the prevalence of AMD will continue to grow, reaching a maximum risk rate of ~30% at age 75. Since smoking significantly increases the risk of AMD and there is a 20% higher incidence of smoking in veterans than in the general U.S. adult civilian population, the VA system will have to provide care for poten- tially up to 7 million or more AMD cases. Current available treatments focus on the late stage of the disease (choroidal neovascularization; CNV); however, those come with significant risks and only target subpopulations of AMD patients. No treatment is available for early AMD (i>85% of all cases). Thus it is paramount that we learn on how to detect AMD early and develop treatments that allow for early disease prevention. While me- chanistic studies have shown that inflammation and smoking are fundamental components of both forms of AMD, genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing AMD. One of the most detrimental mutations occurs in factor H (fH) an essential inhibi- tor in the complement cascade (fH risk haplotype). Overall, it has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. Here we wish to an- swer two essential questions: 1) do smoking and complement act synergistically in the disease process; and 2) can we target the complement cascade therapeutically in smoking-related pathology. For this proposal we will be guided by our overall hypothesis that pathologic activation of the AP has direct effects on the RPE, generat- ing a permissive cellular environment for AMD pathology. Aim 1 is aimed at determining the smoke-induced complement activation pathway in RPE monolayers. In Aim 2, we will test examine complement levels in se- rum of subjects, correlating levels with haplotype and disease. And finally, our hypothesis will be put to test in vivo in Aim 3. We will use a complement inhibitory strategy using a targeted inhibitor that blocks the alternative complement cascade to interfere with CNV and smoke-induced pathology. Testing the alternative pathway in- hibitor will not only establish its therapeutic value, but in addition, elucidating its mechanisms in animal models will investigate the roles and contributions of the alternative pathway of complement in AMD pathology. Taken together, the objective of the current Merit Review proposal is to further characterize the interaction between complement activation and smoking; whereas the long-term goal is to develop a new treatment to reduce the number of AMD cases and improve veteran care and quality of life. Following the successful completion of the experiments described here we would want to initiate follow-up studies in larger animal models of AMD, ex- plore the pharmacokinetics and toxicology of the compound, to ultimately be prepared to proceed to human clinical trials.