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

描述(由申请人提供)： 项目概述老年性黄斑变性(AMD)是一种进展缓慢的多因素疾病，涉及遗传异常和环境侮辱。老年性黄斑变性是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~30%的最大风险比率。由于吸烟大大增加了患AMD的风险，而且退伍军人的吸烟率比普通美国成年平民高出20%，退伍军人管理局系统将不得不为多达700万或更多的AMD病例提供护理。目前可用的治疗方法主要集中在疾病的晚期(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。早期AMD尚无治疗方法(I&GT；占所有病例的85%)。因此，我们学习如何及早发现AMD并开发能够及早预防疾病的治疗方法是至关重要的。虽然机制研究表明炎症和吸烟是这两种形式AMD的基本成分，但遗传学研究表明，不同补体蛋白的多态都会增加AMD的风险。最有害的突变之一发生在因子H(Fh)中，它是补体级联中的基本抑制因子(Fh风险单倍型)。总体而言，有人假设，补体驱动的炎症控制不足可能是AMD疾病发病的主要因素。在这里，我们想回答两个基本问题：1)吸烟和补体在疾病过程中是否起协同作用；2)我们能否在吸烟相关的病理中针对补体级联进行治疗。对于这一提议，我们将遵循我们的总体假设，即AP的病理性激活直接影响RPE，为AMD病理产生一个允许的细胞环境。目的1研究吸烟诱导的RPE单层补体活化途径。在目标2中，我们将检测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。我们将使用一种补体抑制策略，使用一种靶向抑制剂来阻止替代补体级联，以干扰CNV和烟雾诱导的病理。检测替代途径抑制物不仅将确定其治疗价值，而且在动物模型中阐明其机制将探讨补体替代途径在AMD病理中的作用和贡献。综上所述，当前功绩审查提案的目标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病例的数量，并改善退伍军人护理和生活质量。在这里描述的实验成功完成后，我们希望在AMD的更大动物模型中启动后续研究，解释该化合物的药代动力学和毒理学，最终为进入人类临床试验做准备。

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.