Monocytes in Dry Age-Related Macular Degeneration

干性年龄相关性黄斑变性中的单核细胞

• 批准号: 9384973
• 负责人: Eleonora Georgeta Lad
• 金额: $ 13.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384973
• 关键词: Advisory Committees; Affect; Age; Age related macular degeneration; Autopsy; Award; Biological; Biological Markers; Blindness; Blood; Cells; Central Nervous System Degenerative Diseases; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Color; Cone; Contrast Sensitivity; Dark Adaptation; Defect; Development; Disease; Disease Progression; Doctor of Philosophy; Drusen; Elderly; Environment; Exudative age-related macular degeneration; Eye; Fellowship; Flow Cytometry; Frequencies; Functional disorder; Funding; Gene Expression Profiling; Goals; Grant; Histopathology; Image; Impairment; Incidence; Individual; Infiltration; Inflammation; K-Series Research Career Programs; Knowledge; Measures; Mentors; Mentorship; Microscopy; Neurosciences; Ocular Pathology; Ophthalmologist; Optical Coherence Tomography; Pathogenesis; Pathology; Patients; Pattern; Photoreceptors; Recruitment Activity; Research; Research Personnel; Resources; Retina; Retinal; Risk; Role; Scientist; Series; Specimen; Staging; Suggestion; Synapses; Testing; Training; Vision; Visual; Visual Acuity; age related; biomarker development; blood-based biomarker; career; career development; experience; eye center; geographic atrophy; high risk; imaging biomarker; innovation; interest; luminance; macrophage; monocyte; neuroinflammation; novel; outer plexiform layer; photonics; progression marker; responsible research conduct; retinal damage; skills; therapeutic development; therapeutic target

PROJECT SUMMARY Candidate: I am a fellowship-trained retinal ophthalmologist with the long-term career goal of becoming an independent clinician scientist and nationally recognized leader in the field of age-related macular degeneration (AMD). My research agenda is focused on understanding the pathobiology of AMD and developing novel endpoints for clinical trials, biomarkers of disease progression, and therapeutic targets. I have a PhD in neuroscience and a longstanding interest in age-related degenerative diseases of the central nervous system and retina. My immediate career development goal in the current proposal is to characterize the monocytic cells the retina of AMD histopathology specimens and the association of monocytes with biomarkers of disease progression (imaging in autopsy eyes and clinical patients; visual fuction biomarkers in clinical patients). With a K23 mentored award, I would acquire additional didactic training and mentored research experience in in ocular pathology, microscopy, photonics, retinal imaging, clinical research, and responsible conduct of research. Environment: The mentorship and expertise of the advisory committee, the extensive resources of the Duke Eye Center and the Pathology department, and the significant institutional commitment will provide me with the support needed to transition successfully into an independent research career. Research: The focus of this grant is to investigate the hypothesis that infiltration of CD163+ macrophages into the outer retina in dry AMD will correlate with synaptic defects, possibly explaining some of the loss of visual function in these patients. We will assess whether infiltrating subretinal macrophages may be associated or may themselves be the structural features on retinal imaging known to be associated with disease progression. We will also evaluate whether high frequency of monocytes in the blood of patients will correlate with visual dysfunction and retinal imaging biomarkers, suggesting that retinal macrophages are derived from recruited circulating monocytes. In Specific Aim 1, using histopathological analysis of postmortem eyes with HRD, 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 SD-OCT and SLO markers of pseudodrusen. In Specific Aim 2, using analysis of circulating monocytes by flow cytometry in subjects with dry AMD, we will show that the ratio of monocytes subtypes in the blood will correlate with the presence of imaging markers of disease progression and with visual function deficits of low luminance visual acuity, dark adaptation, cone contrast sensitivity and microperimetry testing. We will also isolate blood monocytes and perform analyses of gene expression to identify factors that may contribute to loss of vision. This body of work, which will constitute the basis of an R01 grant, will allow the discovery of new biomarkers of AMD progression and therapeutic targets involving macrophages.

项目摘要 候选人：我是受过奖学金培训的视网膜眼科医生，其长期职业目标是成为一个 独立的临床医生科学家和与年龄相关的黄斑领域的全国认可领导者 变性（AMD）。我的研究议程专注于理解AMD和AMD的病理生物学 为临床试验，疾病进展的生物标志物和治疗靶标开发新的终点。我 在神经科学领域拥有博士学位，并长期对中央年龄相关的退行性疾病感兴趣 神经系统和视网膜。我在当前建议中的直接职业发展目标是表征 单核细胞AMD组织病理学标本的视网膜和单核细胞与 疾病进展的生物标志物（尸检眼和临床患者的成像；视觉融合生物标志物 临床患者）。获得K23指导奖，我将获得其他教学培训并进行指导 眼科病理学，显微镜，光子学，视网膜成像，临床研究和 负责任的研究。 环境：咨询委员会的指导和专业知识，公爵的广泛资源 眼中中心和病理部门以及重大的机构承诺将为我提供 成功过渡到独立研究职业所需的支持。 研究：这笔赠款的重点是研究CD163+巨噬细胞浸润到 干燥AMD中的外视网膜将与突触缺陷相关，可能解释了视觉的某些丧失 这些患者的功能。我们将评估浸润的视网膜下巨噬细胞是否可能相关或 本身可能是视网膜成像中已知与疾病进展相关的结构特征。 我们还将评估患者血液中的高频单核细胞是否与视觉相关 功能障碍和视网膜成像生物标志物，表明视网膜巨噬细胞源自招募 循环单核细胞。在特定的目标1中，使用HRD对死后眼的组织病理学分析，我们 将表明，外部视网膜和视网膜下巨噬细胞的高频与 与年龄匹配的对照眼相比 带有伪曲鲁森的SD-OCT和SLO标记。在特定的目标2中，使用循环单核细胞分析 在患有干AMD受试者的流式细胞仪中，我们将表明血液中的单核细胞亚型的比率将会 与疾病进展的成像标记和低视觉功能缺陷相关 亮度视力，深色适应性，锥形对比度灵敏度和微量工测试。我们也会 分离血液单核细胞并对基因表达进行分析，以识别可能有助于 视力丧失。这项工作将构成R01赠款的基础，将允许发现新的工作 AMD进展和涉及巨噬细胞的治疗靶标的生物标志物。