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: 10615728
• 负责人: ANNE M. LYNCH
• 金额: $ 39.86万
• 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/10615728
• 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; Visual; 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; progression risk; 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.

项目总结/摘要 视网膜相关性黄斑变性（AMD），一种主要影响黄斑区域的慢性多因素疾病 是导致老年人视力下降的主要原因。AMD是一种光感受器支持的疾病 系统与局部炎症事件和补体激活促进基因相关。除了小 在晚期AMD的研究中，系统评估炎症在AMD中的意义还没有 得到了充分的处理。这对于患有中期AMD（iAMD）的患者尤其如此，iAMD是AMD的早期形式。 AMD，我们认为全身炎症的存在可能是iAMD进展的危险因素 严重AMD的视觉威胁。为了解决这一知识差距，我们进行了试点研究， 评价循环炎性标志物包括补体、细胞因子、趋化因子和 我们在科罗拉多AMD登记处招募的iAMD患者中检测高敏C反应蛋白（hsCRP）。我们 发现令人信服的证据表明，某些炎症生物标志物区分了患有和不患有iAMD的患者， 最重要的是发展为晚期AMD的iAMD患者。此外，我们在iAMD中发现， 患者hsCRP的系统水平之间的显着联系，和脉络膜变薄的光学相干性 在一些实施方案中，AMD是通过X射线断层摄影术（OCT）进行的，这是与AMD相关的病理事件之一的发现。总的来说，这些 研究结果表明，按照我们的建议，研究iAMD可以为AMD的早期病理事件提供见解 并且还允许识别那些处于严重AMD和进行性视力丧失的最高风险的人。的目的 拟议的研究是为了证实和扩大我们的新的试点数据的结果，在一个充分的 iAMD队列研究，并探讨我们的假设，即在iAMD患者中， 将识别将转化为晚期AMD的患者。我们将利用现有的 与人口统计学和流行病学数据以及DNA相关的纵向血液样本，多模态图像， 和结果数据。我们将以两个具体目标来论述这一假设。在目标1中，我们将遵循iAMD a）确定最好区分患有炎症性疾病的患者的炎症生物标志物的概况， 发展为晚期AMD的iAMD患者，和B）开发AMD发展的动态风险评分， 结合了AMD流行病学、新定义的炎症特征和遗传风险因素。在目标2中，我们将 重点关注先前确定为AMD进展风险因素的OCT成像生物标志物。我们将 确定循环炎性生物标志物和定性（例如，网状 假性玻璃疣）和定量（例如，玻璃疣体积和脉络膜厚度）测量。我们希望我们的研究 将在iAMD中显示出全身炎症的重要作用。这项研究将提供一个更好的机会， 了解iAMD发病机制以及早期识别高危人群，其中 可以开发有针对性的干预措施，通过预防iAMD来中断AMD的自然病程， 进展为晚期AMD和视力丧失。