The role of astrocytes in the pathogenesis of sporadic tauopathy

星形胶质细胞在散发性 tau 蛋白病发病机制中的作用

基本信息

批准号：
10387292
负责人：
Kristen Whitney
金额：
$ 7.21万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-05 至 2025-12-04
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387292
关键词：
17q21 3-Dimensional Alzheimer&apos s Disease Amyloid Astrocytes Autopsy Behavioral Biochemical Biological Models Brain Cell Death Cells Cellular Morphology Clinical Collection Complex Data Development Disease Disease Progression Disease model Endoplasmic Reticulum Environment Eukaryotic Initiation Factor-2 Event Fellowship Fibroblasts Genetic Genomics Gliosis Goals Histological Techniques Human Image Impaired cognition Laboratories MAPT gene Measurement Measures Mentorship Methods Modeling Molecular Morphology Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurologic Deficit Neurons Organoids Paralysed Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Play Population Positioning Attribute Production Progressive Supranuclear Palsy Proteins Research Research Personnel Research Training Risk Role Secondary to Series Specimen Stains Syndrome Tauopathies Testing Therapeutic Training Translational Research Up-Regulation Variant Work abeta accumulation brain cell brain tissue endoplasmic reticulum stress engineered stem cells gaze genome wide association study human disease induced pluripotent stem cell innovation insight monolayer neuron loss neuropathology novel novel strategies response sensor skills stem cell biology stem cell model stressor tau Proteins tau aggregation tau-1 tool transcriptomics

项目摘要

PROJECT SUMMARY Tauopathies are a group of heterogeneous neurodegenerative diseases characterized by pathological aggregation of tau protein in the brain. The most common primary tauopathy, progressive supranuclear palsy (PSP), is identified clinically by progressive parkinsonism with supranuclear gaze paralysis, cognitive dysfunction, behavioral changes, and other neurological deficits. Neuropathologically, PSP has a constellation of features including morphologically distinct tufted astrocytes (TA). Astrocytes normally do not contain significant levels of tau suggesting that TA play an important, but unknown, pathological role in PSP. The majority of PSP cases are sporadic. Genome wide association studies have identified common variants associated with PSP risk in EIF2AK3, which encodes an endoplasmic reticulum (ER) stress sensor critical for the unfolded protein response (UPR). There is evidence for a pathogenic association between ER stress in astrocytes and tau accumulation in PSP, but to test candidate molecular mechanisms there is a critical need for a model system that recapitulates the cellular environment of the human brain and retains the genetic complexity of human disease. Developing human induced pluripotent stem cell (iPSC)-derived models generated from PSP patients will be a powerful tool to characterize molecular drivers of sporadic tauopathy. We hypothesize that UPR activation in astrocytes drives neurodegeneration and plays a key role in sporadic PSP. In our first aim, we will correlate UPR activation with astrocyte pathology and degeneration in human post-mortem brain tissue. Autopsy-confirmed PSP brain tissue from our large collection will be stained, imaged, and analyzed for p-tau distribution and UPR colocalization using innovative quantitative approaches. In the second aim, we will test the hypothesis that PSP neurons and astrocytes are highly vulnerable to tau pathology, and that UPR activation in PSP astrocytes increases cell vulnerability. To accomplish this aim, we will create patient iPSC-derived monolayer neurons and astrocytes and directly measure molecular changes and cell vulnerability by pharmacological manipulation of the UPR. Lastly, we will determine the extent to which UPR activation in astrocytes increases the production of toxic tau species and cell vulnerability in an iPSC-derived organoid model of sporadic PSP. This aim will explore molecular perturbations in different cell populations that contribute to the development of tau pathology in a 3-D cellular environment that recapitulates the complex neuronal-astrocyte interactions that occur in human brain tissue. These findings will be validated in paired autopsy brain tissue from the same donor. In summary, the clinical-translational research performed in this study will generate patient- derived iPSC models that retain a disease-relevant genomic background and reveal candidate pathways that are disrupted early in sporadic PSP.

项目概要 Tau蛋白病是一组异质性神经退行性疾病，其特征是病理学特征 tau 蛋白在大脑中聚集。最常见的原发性 tau 蛋白病，进行性核上性麻痹 (PSP)，临床上被诊断为进行性帕金森病，伴有核上性凝视麻痹、认知障碍功能障碍、行为改变和其他神经缺陷。在神经病理学上，PSP 有一个星座特征包括形态上不同的簇状星形胶质细胞（TA）。星形胶质细胞通常不含有显着的 tau 水平表明 TA 在 PSP 中发挥重要但未知的病理作用。大部分PSP 病例是零星的。全基因组关联研究已确定与 PSP 风险相关的常见变异 EIF2AK3 编码对未折叠蛋白至关重要的内质网 (ER) 应激传感器回应（普遍定期审议）。有证据表明星形胶质细胞的 ER 应激与 tau 蛋白之间存在致病关联 PSP 中的积累，但为了测试候选分子机制，迫切需要一个模型系统再现了人类大脑的细胞环境并保留了人类的遗传复杂性疾病。开发源自 PSP 患者的人类诱导多能干细胞 (iPSC) 衍生模型将成为表征散发性 tau 蛋白病分子驱动因素的有力工具。我们假设 UPR 星形胶质细胞的激活会导致神经退行性变，并在散发性 PSP 中发挥关键作用。在我们的第一个目标中，我们将将 UPR 激活与人类死后脑组织中的星形胶质细胞病理学和退化相关联。来自我们大量收集的经尸检确认的 PSP 脑组织将被染色、成像并分析 p-tau 使用创新的定量方法进行分布和 UPR 共定位。在第二个目标中，我们将测试假设 PSP 神经元和星形胶质细胞非常容易受到 tau 蛋白病理的影响，并且 UPR 激活 PSP 星形胶质细胞增加了细胞的脆弱性。为了实现这一目标，我们将创建源自患者的 iPSC 单层神经元和星形胶质细胞，直接测量分子变化和细胞脆弱性 UPR 的药理学操作。最后，我们将确定 UPR 激活的程度在 iPSC 衍生的类器官模型中，星形胶质细胞增加了有毒 tau 物质的产生和细胞脆弱性零星的PSP。该目标将探索不同细胞群中的分子扰动，这些扰动有助于 3D 细胞环境中 tau 病理学的发展，概括了复杂的神经元-星形胶质细胞人类大脑组织中发生的相互作用。这些发现将在配对尸检脑组织中得到验证同一个捐赠者。总之，本研究中进行的临床转化研究将产生患者- 衍生的 iPSC 模型保留了疾病相关的基因组背景并揭示了候选途径在零星的 PSP 早期就被破坏。