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: 10012438
• 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/10012438
• 关键词: Affect; Age; Age related macular degeneration; Autopsy; Biological; Biological Markers; Biomedical Engineering; Biometry; Blindness; Cellular Structures; 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; Measures; Mediating; Nonexudative age-related macular degeneration; Ophthalmology; Optical Coherence Tomography; Outcome; Pathogenesis; Pathology; Patients; Peripheral; Photoreceptors; Physiology; Population; Psychophysics; Research; Resolution; Retina; Risk; Role; Series; Specimen; Staging; Structure; Suggestion; Synapses; System; Testing; Therapeutic; Veterans; Vision; Visual; Visual Acuity; Work; biomarker development; biomarker identification; blood-based biomarker; care burden; cost; cytokine; falls; geographic atrophy; high risk; imaging biomarker; intravitreal injection; luminance; macrophage; monocyte; neurotoxicity; novel; outer plexiform layer; peripheral blood; recruit; retinal damage; retinal imaging; standard of care; therapeutic target

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.

年龄相关性黄斑变性（AMD）是导致老年人失明的主要原因 美国有超过一百万45岁以上的退伍军人，造成了巨大的护理负担。这 该拟议项目的目标是研究视网膜巨噬细胞的作用及其与功能的关系 以及干性年龄相关性黄斑变性 (AMD) 疾病进展的结构生物标志物， AMD 的常见形式 (85%)，目前尚无治愈方法。视网膜成像和血液成像的发展 识别 HRD 患者将进展为 NVAMD 和 GA 的生物标志物非常重要，因为这些 需要设计新的 AMD 疗法的临床试验，使 VA 人群受益。我们的 建立的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，具有研究病理学和各类疾病的记录 AMD 的生物标志物。 我们的假设是 CD163+ 巨噬细胞浸润到患有以下疾病的患者的外视网膜： 中度干性 AMD 与突触缺陷相关，这可能解释了这些患者视觉功能的丧失 患者。我们将评估浸润性视网膜下巨噬细胞是否可能相关或可能本身 代表疾病进展的谱域光学相干断层扫描 (SD-OCT) 生物标志物， 特别是网状假玻璃膜疣和高反射灶。我们还将评估是否出现高频 外周血 CD163+ 单核细胞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， 通过对患有中度 AMD 和高风险玻璃疣的死后眼睛进行组织病理学分析，我们将 证明视网膜外层和视网膜下巨噬细胞的高频率与视网膜标记物相关 与年龄匹配的对照眼相比，损伤（尤其是感光突触受损） 网状假玻璃膜疣的影像学标志物。在 SA2 中，通过流式细胞术分析循环单核细胞 在患有干性AMD的受试者中，我们将证明外周血CD163+单核细胞的高表达 中度干性 AMD 患者将与疾病进展的 SD-OCT 标记物的存在相关联， 心理物理测试中的视觉功能缺陷。在 SA3 中，我们还将从血液中分离单核细胞， 死后视网膜，对基因表达和释放的已知介导突触的细胞因子进行分析 功能障碍和神经毒性，目的是确定可能导致视力丧失的因素。 这项工作将产生关于 CD163+ 巨噬细胞在 AMD患者患有高危玻璃膜疣。我们的结果将能够表明浸润巨噬细胞是 眼睛疾病进展的成像生物标志物与中间形式的结构相关性 疾病。这项研究将使外周单核细胞亚群的功能表征成为可能 揭示它们在 AMD 发病机制和进展中的潜在作用。重要的是，这项工作将有助于 开发新的临床试验终点、识别疾病进展的生物标志物以及 治疗目标将改变受 AMD 影响的老年退伍军人的护理标准。