Single-Cell Transcriptomic Analysis of Human Retina

人类视网膜的单细胞转录组分析

• 批准号: 10119528
• 负责人: Mingyao Li
• 金额: $ 41.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119528
• 关键词: Adult; Affect; Alabama; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anatomy; Animal Model; Animals; Astrocytes; Autopsy; Axon; Axonal Transport; Biological Markers; Blood Vessels; Blood-Retinal Barrier; Brain; Cell Nucleus; Cells; Chromium; Clinical; Cognitive deficits; Coupled; Data; Data Set; Deposition; Development; Diagnosis; Disease Progression; Eye; Eye Banks; Funding; Future; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Genomics; Geographic Locations; Goals; Histologic; Homeostasis; Hour; Human; Image; Immune; Individual; Interneurons; Location; Maintenance; Maps; Measures; Memory Loss; Microglia; Molecular; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Optic Nerve; Optical Coherence Tomography; Parents; Pathologic; Patients; Peripheral; Photoreceptors; Pilot Projects; Play; Population; Recovery; Regulation; Research; Retina; Retinal Ganglion Cells; Retinal macula; Role; Senile Plaques; Spatial Distribution; Structure; Testing; Thalamic structure; Thinness; Tissues; Transcript; Variant; Visual; cell type; extracellular; hyperphosphorylated tau; macula; nervous system disorder; neuroinflammation; response; retinal nerve fiber layer; retinal neuron; screening; single-cell RNA sequencing; tau Proteins; transcriptome sequencing; transcriptomics; vascular abnormality

PROJECT SUMMARY Alzheimer's Disease (AD) is a progressive neurodegenerative disease that affects 5.2 million Americans and 35 million worldwide. Pathologically, AD is characterized by deposits of extra-cellular amyloid plaques and neurofibrillary tangles. The retina and the brain have been found to be associated with a range of neurological diseases including AD and respond similarly to neuropathological conditions. Mounting evidence has suggested that AD also results in visual deficits, and pathological changes in the retinas of AD patients that include extensive loss of optic nerve and retinal ganglion cells, thinning of the retinal nerve fiber layer, and vascular abnormalities. As a projection of the central nervous system, the retina shares many cell types found in the brain including neurons, astrocytes, microglia, microvasculature, and a blood-retina barrier. Amyloid precursor protein is synthesized in retinal ganglion cells and is transported by the axons of the optic nerve to the brain. Additional proteins of the amyloid cascade are expressed by retinal neurons and glia. Further, amyloid beta plaques have been described in all retinal layers in animal models of AD. Histologically in humans, there is evidence of retinal thinning in AD patients and amyloid plaques in postmortem retinas of patients with early stage AD. Despite increasing evidence of retina involvement in AD, the underlying molecular and cellular mechanisms for these changes in the retina are still poorly understood. Another important factor in AD is the role of neuroinflammation. Although neuroinflammatory responses are commonly described in the brain of AD patients and animal models, only few studies have described retinal glia alterations in AD. In this project, we will test the hypothesis that measureable anatomical and molecular deficits occur in the retinas of individuals diagnosed with AD, and the retinal gene expression changes correlate with gene expression changes in the brain of individuals diagnosed with AD. Collaborating with the Alabama Eye Bank, the leader in rapid eye tissue recovery, we will perform single-cell RNA sequencing coupled to Spatial Transriptomics of the human retina in postmortem donors with AD, with the goal of identifying cells that are contributing to the development of AD pathology in the retina. Results from this pilot study will allow us to have a better understanding on the molecular and cellular variations of retinal changes in AD.

项目摘要 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，影响520万美国人和 全球3500万。从病理上讲，AD的特征是细胞外淀粉样斑块的沉积物和 神经纤维缠结。发现视网膜和大脑与一系列神经系统有关 包括AD在内的疾病和对神经病理状况的反应类似。越来越多的证据有 建议AD还会导致视觉缺陷，以及AD患者视网膜的病理变化， 包括大量丧失视神经和视网膜神经节细胞，视网膜神经纤维层的变薄，以及 血管异常。作为中枢神经系统的投影，Retina共享了许多细胞类型 在大脑中，包括神经元，星形胶质细胞，小胶质细胞，微脉管系统和血液屏障。淀粉样蛋白 前体蛋白在视网膜神经节细胞中合成，并由视神经的轴突传输到 大脑。淀粉样蛋白酶的其他蛋白质通过视网膜神经元和神经胶质表达。更远， 在AD动物模型中，在所有视网膜层中都描述了淀粉样蛋白β斑块。组织学上 人类，有证据表明AD患者的视网膜变薄和淀粉样斑块的邮政在事后视网膜中 早期广告的患者。尽管越来越多的视网膜参与AD的证据，但基础 视网膜中这些变化的分子和细胞机制仍然鲜为人知。其他 AD的重要因素是神经炎症的作用。尽管神经炎症反应通常是 在AD患者和动物模型的大脑中描述，只有很少的研究描述了视网膜胶质 AD的改变。在这个项目中，我们将测试可测量的解剖学和分子缺陷的假设 发生在被诊断为AD的个体的视网膜中，视网膜基因表达的变化与 基因表达在被诊断为AD的个体的大脑中变化。与阿拉巴马州合作 银行是快速眼组织恢复的领导者，我们将执行与空间相结合的单细胞RNA测序 人类视网膜在具有AD的后捐赠者中的人性视网膜的跨误复学，目的是鉴定细胞 为视网膜中的AD病理发展做出贡献。这项试验研究的结果将使我们能够拥有 对AD视网膜变化的分子和细胞变化有了更好的了解。