Molecular Risk Factors for Age-Related Maculopathy

描述（由申请人提供）：这是一项新研究者的修订申请，旨在评估炎症在年龄相关性黄斑病变（ARM）中的作用。ARM是美国和其他发达国家老年人不可治愈失明的主要原因。然而，参与ARM发病机制的基本分子途径仍然未知，很少有潜在的可改变的风险因素已被确定，治疗仍然不足。我们假设，在ARM的早期和晚期阶段发生的病理变化是由与炎症相关的细胞和分子介导的，并且引起这些变化的促炎状态至少部分是全身性的，而不仅仅是局部现象。拟议的研究将建立在基础广泛和不断增长的研究基础上，这些研究支持炎症/免疫介导的过程在ARM发病机制中的关键作用。这项研究表明，炎症可以通过几种途径介导ARM的发展，包括RPE损伤和修复，玻璃疣形成，Bruch膜变性，脉络膜血管内皮功能障碍，氧化应激增加，抗氧化剂生物利用度降低，以及直接或间接促进血管生成。通过使用来自医生健康研究、妇女健康研究、妇女抗氧化心血管疾病研究、护士健康研究和卫生专业人员随访研究的存档血液标本，该提案代表了一种非常具有成本效益和效率的方法，可以使用前瞻性巢式病例对照研究设计来调查所提出的假设。 具体目的是研究1）全身性炎症标志物/介质之间的关系（IL-6、C-反应蛋白、纤维蛋白原、触珠蛋白、循环粘附分子和肿瘤坏死因子-α受体）与事件ARM的关系，2）这些炎性分子与干性和新生血管性ARM病变的单独关系，3）炎症与ARM的关系是否独立于其他危险因素，如吸烟，和4）的方法生物标志物之间的相互关系，并独立预测事件ARM。这些目标将通过测量实现使用高度在基线时（即ARM发生前）采集并自那时起储存在-80 ℃以下的血液标本中炎症生物标志物的灵敏测定。将在最终发生ARM的受试者和未发生ARM的对照受试者中比较生物标志物水平，并将分析扩展至控制其他风险因素。这项研究的长期目标和临床意义是阐明ARM发病机制的潜在潜在生物学机制，并提出新的预防或治疗方法的途径，以及确定临床上有用的生物标志物，用于识别ARM风险增加的个体。

DESCRIPTION (provided by applicant): This is a revised application by a new investigator to assess the role of inflammation in age-related maculopathy (ARM). ARM comprises the leading cause of incurable blindness among older adults in the US and other developed countries. However, the basic molecular pathways involved in the pathogenesis of ARM remain unknown, few potentially modifiable risk factors have been identified, and treatment remains inadequate. We hypothesize that the pathologic changes occurring in both the early and late stages of ARM are mediated by cells and molecules associated with inflammation and that the pro-inflammatory state that gives rise to these changes is at least in part a systemic rather than merely local phenomenon. The proposed studies will build upon a broadly based and growing body of research that supports a key role for inflammatory/immune-mediated processes in ARM pathogenesis. This research suggests several pathways through which inflammation could mediate the development of ARM, including RPE damage and repair, drusen formation, degeneration of Bruch's membrane, endothelial dysfunction in choroidal vessels, increased oxidative stress, decreased bioavailability of antioxidants, as well as the direct or indirect promotion of angiogenesis. Through its use of archived blood specimens from the Physicians' Health Study, Women's Health Study, women's Antioxidant Cardiovascular Disease Study, Nurses' Health Study, and Health Professionals Follow-up Study, this proposal represents an exceptionally cost-effective and efficient means to investigate the proposed hypothesis using a prospective nested case-control study design. The Specific Aims are to investigate 1) the relationship of systemic markers /mediators of inflammation (IL-6, C-reactive protein, fibrinogen, haptoglobin, circulating adhesion molecules, and tumor necrosis factor-alpha receptors) with incident ARM, 2) the separate relationships of these inflammatory molecules with dry and neovascular ARM lesions, 3) whether the relationship of inflammation with ARM is independent of other risk factors such as cigarette smoking, and 4) the interrelationships among the biomarkers and which independendy predict incident ARM. These aims will be accomplished through measurement using highly sensitive assays of inflammatory biomarkers in blood specimens collected at baseline (i.e. prior to the development of ARM) and stored since that time below -80¿C. Biomarker levels will be compared among subjects who eventually developed ARM and control subjects who remained free of ARM, and the analysis will be extended to control for other risk factors. The long-term objective and clinical relevance of this research is to shed light on potential underlying biological mechanisms of ARM pathogenesis and suggest avenues for new preventive or therapeutic approaches, as well as to identify clinically useful biomarkers for identification of individuals at increased risk of ARM.