Biomarkers of Systemic Inflammation in Intermediate Age-Related Macular Degeneration

中度年龄相关性黄斑变性全身炎症的生物标志物

• 批准号: 10388398
• 负责人: ANNE M. LYNCH
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388398
• 关键词: Address; Advanced Development; Affect; Age related macular degeneration; Anti-Inflammatory Agents; Biological Markers; Blindness; Blood; Blood specimen; C-reactive protein; Chronic; Chronic Disease; Clinical; Colorado; Complement; Complement Activation; DNA; Data; Development; Disease; Drusen; Early identification; Elderly; Epidemiology; Event; Exudative age-related macular degeneration; Future; Genes; Genetic; Genetic Risk; Goals; Individual; Inflammaging; Inflammation; Inflammatory; Interruption; Intervention; Knowledge; Link; Longitudinal cohort; Measures; Multimodal Imaging; Natural History; Obesity; Optical Coherence Tomography; Other Genetics; Outcome; Pathogenesis; Pathologic; Patients; Photoreceptors; Pilot Projects; Play; Prevention strategy; Process; Registries; Research; Retina; Risk; Risk Factors; Role; Secondary Prevention; Support System; Therapeutic Intervention; Thick; Thinness; Time; Vision; chemokine; circulating biomarkers; clinical risk; cohort; comorbidity; complement system; cytokine; epidemiologic data; genetic risk factor; genetic variant; geographic atrophy; healthy lifestyle; high risk; high risk population; imaging biomarker; inflammatory marker; insight; macula; novel; older patient; personalized approach; prevent; preventive intervention; recruit; systemic inflammatory response; targeted treatment

PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD), a chronic multifactorial disease primarily affecting the macula region of the retina, is a leading cause of vision loss in the elderly. AMD is a disease of the photoreceptor support system linked with local inflammatory events and complement activation-promotion genes. Apart from a small number of studies in advanced AMD, the significance of systemically assessed inflammation in AMD has not been adequately addressed. This is especially true for patients with intermediate AMD (iAMD), an early form of AMD, where we suggest that the presence of systemic inflammation may be a risk factor for iAMD progression to the visually threatening forms of advanced AMD. To address this knowledge gap, we conducted pilot studies to evaluate profiles of circulating inflammatory markers including complement, cytokines, chemokines, and high-sensitivity C-reactive protein (hsCRP) in patients with iAMD recruited into our Colorado AMD registry. We found compelling evidence that certain inflammatory biomarkers distinguished patients with and without iAMD, and most importantly patients with iAMD who progressed to advanced AMD. Furthermore, we found in iAMD patients a significant link between systemic levels of hsCRP, and choroidal thinning on optical coherence tomography (OCT), a finding which is one of the pathological events linked with AMD. In aggregate, these findings suggest that studying iAMD as we propose, can provide insights into early pathologic events in AMD and also allow one to identify those at highest risk for severe AMD and progressive visual loss. The purpose of the proposed study is to corroborate and expand on the findings from our novel pilot data in an adequately powered iAMD cohort and explore our hypothesis that among patients with iAMD an inflammatory biomarker profile will identify patients who will convert to advanced AMD. We will leverage our cohort's existing longitudinal blood samples linked to demographic and epidemiology data as well as DNA, multimodal image, and outcome data. We will address this hypothesis with two specific aims. In Aim 1 we will follow an iAMD cohort over time and, a) Identify the profile of inflammatory biomarkers that best distinguishes patients with iAMD who progress to advanced AMD, and b) Develop a dynamic risk score for AMD progression that combines AMD epidemiological, newly defined inflammatory profiles, and genetic risk factors. In Aim 2, we will focus on OCT imaging biomarkers previously established as risk factors for AMD progression. We will determine the relationships between circulating inflammatory biomarkers and both qualitative (e.g., reticular pseudodrusen) and quantitative (e.g., drusen volume and choroidal thickness) measures. We expect our study will show an important role for systemic inflammation in iAMD. This study will present an opportunity to better understand iAMD pathogenesis as well as for early identification of a high-risk group of individuals in which targeted interventions can be developed to interrupt the natural history of AMD by preventing iAMD progression to advanced AMD and vision loss.

项目摘要/摘要 与年龄相关的黄斑变性（AMD），这是一种主要影响黄斑区域的慢性多因素疾病 视网膜是老年人视力丧失的主要原因。 AMD是感光器支持的疾病 与局部炎症事件和补体激活促进基因相关的系统。除了一个小 高级AMD的研究数量，AMD中系统评估的炎症的重要性尚未 已经充分解决了。对于中级AMD（IAMD）的患者尤其如此，这是一种早期形式 AMD，我们认为系统性炎症的存在可能是IAMD进展的危险因素 对视觉威胁的高级AMD形式。为了解决这个知识差距，我们进行了试点研究 评估循环标记物的概况，包括补体，细胞因子，趋化因子和 IAMD患者的高敏性C反应蛋白（HSCRP）招募到我们的科罗拉多AMD注册表中。我们 发现了令人信服的证据，表明某些炎症生物标志物使有或没有IAMD的患者区分患者 最重要的是，患有IAMD的患者已升级为高级AMD。此外，我们在IAMD中发现 患者全身水平的HSCRP和脉络膜上的脉络膜变薄之间存在显着联系 断层扫描（OCT），这是与AMD相关的病理事件之一。总体而言，这些 调查结果表明，按照我们的建议，研究IAMD可以提供对AMD早期病理事件的见解 还允许人们确定严重AMD和进行性视觉丧失的风险最高的人。目的 拟议的研究是确保并扩大了我们新颖的飞行员数据中的发现 动力IAMD队列并探讨了我们的假设，即IAMD患者炎症生物标志物 个人资料将确定将转换为高级AMD的患者。我们将利用我们的队列的现有 与人口统计学和流行病学数据以及DNA，多模式图像有关的纵向血液样本， 和结果数据。我们将以两个具体的目的解决这一假设。在AIM 1中，我们将遵循IAMD 随着时间的流逝，a）确定炎症生物标志物的特征，该炎症生物标志物最能区分患者 进步为AMD的IAMD，b）为AMD进展增长动态风险评分 结合了AMD流行病学，新定义的炎症概况和遗传危险因素。在AIM 2中，我们将 专注于以前确定为AMD进展的风险因素的OCT成像生物标志物。我们将 确定循环炎性生物标志物与定性之间的关系（例如，网状 伪曲线）和定量（例如，drusen的体积和脉络膜厚度）。我们期望我们的研究 将在IAMD中显示出全身性炎症的重要作用。这项研究将提供一个更好的机会 了解IAMD发病机理以及早期鉴定一群高风险的个体 可以通过防止IAMD来开发有针对性的干预措施以中断AMD的自然历史 发展为高级AMD和视力丧失。