Role of Macrophages in Age-Related Macular Degeneration

巨噬细胞在年龄相关性黄斑变性中的作用

• 批准号: 10463562
• 负责人: Eleonora Georgeta Lad
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463562
• 关键词: Affect; Age; Age related macular degeneration; Autopsy; Biological; Biological Markers; Biomedical Engineering; Biometry; Blindness; Clinical; Clinical Trials; Clinical Trials Design; Color; Cone; Dark Adaptation; Defect; Development; Disease; Disease Marker; Disease Progression; Drusen; Elderly; Exudative age-related macular degeneration; Eye; Flow Cytometry; Frequencies; Functional disorder; Gene Expression Profiling; Genes; Goals; Immunology; Impairment; Incidence; Individual; Infiltration; Inflammation; Knowledge; Long-Term Care for Elderly; Macrophage; Measures; Mediating; Nonexudative age-related macular degeneration; Ophthalmology; Optical Coherence Tomography; Outcome; Pathogenesis; Pathology; Patients; Perimetry; Peripheral; Photoreceptors; Physiology; Population; Psychophysics; Research; Resolution; Retina; Risk; Role; Series; Specimen; Staging; Synapses; System; Testing; Therapeutic; Veterans; Vision; Visual Acuity; Work; biomarker development; biomarker identification; blood-based biomarker; care burden; cost; cytokine; falls; geographic atrophy; high risk; imaging biomarker; intravitreal injection; luminance; military veteran; monocyte; neurotoxicity; novel; outer plexiform layer; peripheral blood; recruit; retinal damage; retinal imaging; standard of care; therapeutic target; visual dysfunction

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the US and in more than a million veterans over the age of 45, resulting in a tremendous burden of care. The objective of this proposed project is to investigate the role of retinal macrophages and relationship to functional and structural biomarkers of disease progression in dry age-related macular degeneration (AMD), the most common form of AMD (85%) and currently without cures. Development of retinal imaging and blood-based biomarkers to identify individuals with HRD who will progress to NVAMD and GA is important, as these are required to design clinical trials of novel AMD therapies that will benefit the VA population. Our established team combines expertise in retinal ophthalmology and physiology, immunology, pathology, bioengineering and biostatistics, with a track record of studying the pathobiology and the various classes of biomarkers of AMD. Our hypothesis is that infiltration of CD163+ macrophages into the outer retina in patients with intermediate dry AMD will correlate with synaptic defects, possibly explaining the loss of visual function in these patients. We will assess whether infiltrating subretinal macrophages may be associated or may themselves represent the spectral domain optical coherence tomography (SD-OCT) biomarkers of disease progression, specifically reticular pseudodrusen and hyper-reflective foci. We will also evaluate whether high frequency of peripheral blood CD163+ monocytes will correlate with visual dysfunction and retinal imaging biomarkers, suggesting that retinal CD163+ macrophages are derived from recruited circulating CD163+ monocytes. In SA1, using histopathological analysis of postmortem eyes with intermediate AMD with high risk drusen, we will demonstrate that high frequency of outer retinal and subretinal macrophages is associated with markers of retinal damage (especially disrupted photoreceptor synapses) as compared to age-matched control eyes and with imaging markers of reticular pseudodrusen. In SA2, using analysis of circulating monocytes by flow cytometry in subjects with dry AMD, we will show that high expression of peripheral blood CD163+ monocytes in intermediate dry AMD patients will correlate with the presence of SD-OCT markers of disease progression and visual function deficits on psychophysical tests. In SA3, we will also isolate monocytes from blood and postmortem retina, perform analyses of gene expression and released cytokines known to mediate synaptic dysfunction and neurotoxicity with the goal to identify factors that may contribute to loss of vision. This body of work will generate important new knowledge about the role of CD163+ macrophages in AMD patients with high-risk drusen. Our results will be able to show that infiltrating macrophages are the structural correlates of imaging biomarkers of disease progression in eyes with the intermediate form of the disease. This research will enable functional characterization of peripheral monocyte subpopulations to uncover their potential role in pathogenesis and progression of AMD. Importantly, this work will aid in the development of novel endpoints for clinical trials, identification of biomarkers of disease progression and therapeutic targets that will change the standard of care for elderly veterans affected by AMD.

与年龄相关的黄斑变性（AMD）是老年人失明的主要原因 我们以及45岁以上的一百万退伍军人，导致了巨大的护理负担。这 该提出的项目的目的是研究视网膜巨噬细胞的作用和与功能的关系 与干燥年龄相关黄斑变性（AMD）中疾病进展的结构生物标志物，最多 AMD的常见形式（85％），目前没有治疗方法。视网膜成像和基于血液的发展 生物标志物可以识别将会发展为NVAMD和GA的HRD的人很重要，因为 需要设计将有益于VA人群的新型AMD疗法的临床试验。我们的 成立团队结合了视网膜眼科和生理学，免疫学，病理学， 生物工程和生物统计学，并具有研究病理生物学和各种类别的记录 AMD的生物标志物。 我们的假设是，在患有 中间干AMD将与突触缺陷相关，可能解释了这些视觉功能的丧失 患者。我们将评估浸润的视网膜下巨噬细胞可能是相关的还是自己可能 代表光谱域光学相干断层扫描（SD-OCT）疾病进展的生物标志物， 特异性网状假性曲线和过度反射灶。我们还将评估是否高频 外周血CD163+单核细胞将与视觉功能障碍和视网膜成像生物标志物相关， 表明视网膜CD163+巨噬细胞源自招募的循环CD163+单核细胞。在SA1中 使用具有高风险drusen的中级AMD的死后眼睛的组织病理学分析，我们将 证明外部视网膜和视网膜下巨噬细胞的高频与视网膜标记有关 与年龄匹配的对照眼相比 网状伪曲霉的成像标记。在SA2中，使用流式细胞术对循环单核细胞进行分析 在干燥AMD的受试者中，我们将表明外周血CD163+单核细胞的高表达 中间干AMD患者将与疾病进展的SD-OCT标记和 心理物理测试的视觉功能缺陷。在SA3中，我们还将与血液和 验尸视网膜，进行基因表达的分析并释放出已知可以介导突触的细胞因子 功能障碍和神经毒性的目标是确定可能导致视力丧失的因素。 这项工作将产生有关CD163+巨噬细胞在 AMD患者患有高危drusen。我们的结果将能够表明渗透巨噬细胞是 疾病进展的成像生物标志物在眼睛中的结构相关性与中间形式 疾病。这项研究将使外周单核细胞亚群的功能表征 发现它们在AMD的发病机理和进展中的潜在作用。重要的是，这项工作将有助于 开发用于临床试验的新型终点，鉴定疾病进展的生物标志物和 治疗目标将改变受AMD影响的老年退伍军人的护理标准。