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 阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响520万美国人， 全球3500万在病理学上，AD的特征在于细胞外淀粉样蛋白斑块的沉积， 神经系统缠结已经发现视网膜和大脑与一系列神经系统疾病有关。 包括AD在内的多种疾病，并且对神经病理学病症的反应类似。越来越多的证据表明 提示AD还导致视觉缺陷，以及AD患者视网膜的病理变化， 包括视神经和视网膜神经节细胞的大量丧失，视网膜神经纤维层变薄， 血管异常作为中枢神经系统的投射，视网膜共享发现的许多细胞类型。 包括神经元、星形胶质细胞、小胶质细胞、微血管系统和血视网膜屏障。淀粉样 前体蛋白在视网膜神经节细胞中合成，并由视神经的轴突运输， 大脑淀粉样蛋白级联的其他蛋白质由视网膜神经元和神经胶质表达。此外，本发明还 在AD的动物模型中的所有视网膜层中已经描述了淀粉样β斑块。在组织学 在人类中，有证据表明AD患者的视网膜变薄， 早期AD患者。尽管越来越多的证据表明视网膜参与了AD，但潜在的 视网膜中这些变化的分子和细胞机制仍然知之甚少。另一 AD的重要因素是神经炎症的作用。虽然神经炎症反应通常 在AD患者和动物模型的大脑中描述，只有少数研究描述了视网膜胶质细胞 AD的变化。在这个项目中，我们将测试的假设，可测量的解剖和分子缺陷， 发生在被诊断患有AD的个体的视网膜中，并且视网膜基因表达变化与 基因表达的变化，在大脑中的个人诊断为AD。与亚拉巴马之眼合作 Bank是快速眼组织修复领域的领导者，我们将进行单细胞RNA测序， 在患有AD的死后供体中的人视网膜的Transriptomics，其目标是识别与AD相关的细胞。 有助于视网膜中AD病理学的发展。这项试点研究的结果将使我们能够 更好地了解AD视网膜病变的分子和细胞变化。