Molecular Risk Factors for Age-Related Maculopathy

描述（由申请人提供）：这是一位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无法治愈的失明的主要原因。然而，参与ARM发病机制的基本分子途径仍然未知，已经确定的潜在可改变的危险因素很少，治疗仍然不足。我们假设在早期和晚期发生的病理变化是由与炎症相关的细胞和分子介导的，并且导致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广泛基础和不断增长的研究基础上，这些研究支持炎症/免疫介导过程在ARM发病机制中的关键作用。本研究提示炎症介导ARM的多种途径，包括RPE损伤和修复、drusen形成、Bruch膜变性、脉络膜内皮功能障碍、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。通过使用来自医师健康研究、妇女健康研究、女性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，本建议采用前瞻性巢式病例对照研究设计，代表了一种特别具有成本效益和有效的方法来调查所提出的假设。

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.