Molecular Risk Factors for Age-Related Maculopathy

年龄相关性黄斑病的分子危险因素

• 批准号: 6799179
• 负责人: DEBRA A SCHAUMBERG
• 金额: $ 31.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799179
• 关键词: acute phase protein; aging; biomarker; cell adhesion molecules; clinical chemistry; clinical research; disease /disorder proneness /risk; epidemiology; eye disorder diagnosis; fibrinogen; haptoglobins; human subject; inflammation; interleukin 6; macular degeneration; pathologic process; questionnaires; selectins; tumor necrosis factor alpha; vascular cell adhesion molecule

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.

描述（由申请人提供）：这是一位新研究者修改后的申请，旨在评估炎症在年龄相关性黄斑病 (ARM) 中的作用。 ARM 是导致美国和其他发达国家老年人无法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，几乎没有发现潜在的可改变的危险因素，治疗仍然不充分。我们假设 ARM 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，并且引起这些变化的促炎症状态至少部分是系统性的，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发展的研究基础上，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。这项研究提出了炎症介导 ARM 发展的多种途径，包括 RPE 损伤和修复、玻璃疣形成、布鲁赫膜变性、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、女性健康研究、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样本，该提案代表了一种极其经济高效的方法，可以使用前瞻性巢式病例对照研究设计来研究所提出的假设。 具体目标是研究 1) 炎症的全身标志物/介质（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）与发生 ARM 的关系，2) 这些炎症分子与干性和新生血管 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，4) 生物标志物之间的相互关系，可以独立预测 ARM 事件。这些目标将通过使用在基线（即 ARM 开发之前）收集的血液样本中的炎症生物标志物的高灵敏度测定进行测量来实现，并自那时起储存在 -80°C 以下。将比较最终发生 ARM 的受试者和未发生 ARM 的对照受试者之间的生物标志物水平，并且分析将扩展到控制其他风险因素。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，以识别 ARM 风险增加的个体。

项目成果

Prospective study of inflammatory biomarkers and risk of diabetic retinopathy in the diabetes control and complications trial.

• DOI: 10.1001/jamaophthalmol.2013.2299
• 发表时间: 2013-04
• 期刊: JAMA OPHTHALMOLOGY
• 影响因子: 8.1
• 作者: Muni, Rajeev H.;Kohly, Radha P.;Lee, Eudocia Q.;Manson, JoAnn E.;Semba, Richard D.;Schaumberg, Debra A.
• 通讯作者: Schaumberg, Debra A.