Molecular Risk Factors for Age-Related Maculopathy

描述(由申请人提供)：这是一位新的研究人员修改后的申请，旨在评估炎症在老年性黄斑病变(ARM)中的作用。在美国和其他发达国家，ARM是导致无法治愈的老年人失明的主要原因。然而，参与ARM发病机制的基本分子途径仍不清楚，几乎没有潜在的可改变的危险因素被识别，治疗仍然不充分。我们假设，ARM早期和晚期的病理变化都是由与炎症相关的细胞和分子介导的，导致这些变化的促炎状态至少部分是一种全身现象，而不仅仅是局部现象。拟议的研究将建立在基础广泛且不断增长的研究基础上，这些研究支持炎症/免疫中介过程在ARM发病机制中的关键作用。本研究提示炎症可通过多种途径介导ARM的发展，包括RPE损伤和修复、玻璃体形成、Bruch膜退化、脉络膜血管内皮细胞功能障碍、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。通过使用医生健康研究、妇女健康研究、妇女抗氧化剂心血管疾病研究、护士健康研究和卫生专业人员跟踪研究的存档血液样本，这项建议代表了一种特别具有成本效益和效率的方法，利用前瞻性嵌套病例对照研究设计来调查所提出的假设。 其具体目的是：1)全身炎症标志物/介质(IL-6、C反应蛋白、纤维蛋白原、结合珠蛋白、循环黏附分子和肿瘤坏死因子-α受体)与ARM发病的关系；2)这些炎症分子与干性和新生血管病变的单独关系；3)炎症与ARM的关系是否独立于吸烟等其他危险因素；4)这些生物标志物之间的相互关系以及独立预测ARM发病的因素。这些目标将通过使用在基线(即在ARM发展之前)收集并自那时起储存在-80℃以下的血液样本中的炎性生物标记物的高灵敏度分析来实现。将在最终发展为ARM的受试者和没有ARM的对照受试者之间进行生物标记物水平的比较，分析将扩展到其他风险因素的对照。这项研究的长期目标和临床意义是阐明ARM发病机制的潜在生物学机制，并为新的预防或治疗方法提供途径，以及识别临床上有用的生物标志物，以识别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.