Transcriptomic assessment of pathology in PD with dementia and dementia with Lewy Bodies using iPSC neurons and brain tissue of the same individuals

使用同一个体的 iPSC 神经元和脑组织对帕金森病痴呆和路易体痴呆进行病理学转录组评估

• 批准号: 10511261
• 负责人: Ignazio Stefano Piras
• 金额: $ 42.33万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511261
• 关键词: ATAC-seq; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Astrocytes; Autopsy; Biological Markers; Biological Models; Brain; Brain Pathology; Cell Culture Techniques; Cell Nucleus; Cells; Characteristics; Chromatin Structure; Chromium; Clinical; Clinical Trials; Cytoplasmic Inclusion; Data; Data Set; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Disease Management; Disease Progression; Disease model; Drug Screening; Drug Targeting; Ensure; Event; Frontotemporal Dementia; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Gliosis; Hand; Human; Impaired cognition; Individual; Induced pluripotent stem cell derived neurons; Label; Lewy Bodies; Lewy Body Dementia; Measures; Microglia; Modeling; Molecular; Monitor; Morphology; Motor; Neurofibrillary Tangles; Neuroglia; Neuronal Differentiation; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Phenotype; Prosencephalon; RNA; RNA Transport; RNA metabolism; Regulation; Sample Size; Senile Plaques; Small Nuclear RNA; Structure of middle temporal gyrus; Symptoms; Synapses; System; Technology; Testing; Time; Time Study; Tissue Differentiation; Tissue Sample; Tissues; Work; XCL1 gene; accurate diagnosis; alpha synuclein; base; brain cell; brain tissue; cell type; demographics; disease diagnosis; disease phenotype; genomic platform; improved; individual patient; induced pluripotent stem cell; molecular phenotype; motor impairment; multi-electrode arrays; multiple omics; neuron loss; neuronal excitability; new therapeutic target; novel; novel marker; novel therapeutics; participant enrollment; patient population; patient stratification; protein TDP-43; specific biomarkers; stem cell differentiation; stressor; symptom treatment; synaptic function; tau Proteins; tau-1; transcriptome; transcriptome sequencing; transcriptomics; ATAC-seq; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Astrocytes; Autopsy; Biological Markers; Biological Models; Brain; Brain Pathology; Cell Culture Techniques; Cell Nucleus; Cells; Characteristics; Chromatin Structure; Chromium; Clinical; Clinical Trials; Cytoplasmic Inclusion; Data; Data Set; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Disease Management; Disease Progression; Disease model; Drug Screening; Drug Targeting; Ensure; Event; Frontotemporal Dementia; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Gliosis; Hand; Human; Impaired cognition; Individual; Induced pluripotent stem cell derived neurons; Label; Lewy Bodies; Lewy Body Dementia; Measures; Microglia; Modeling; Molecular; Monitor; Morphology; Motor; Neurofibrillary Tangles; Neuroglia; Neuronal Differentiation; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Phenotype; Prosencephalon; RNA; RNA Transport; RNA metabolism; Regulation; Sample Size; Senile Plaques; Small Nuclear RNA; Structure of middle temporal gyrus; Symptoms; Synapses; System; Technology; Testing; Time; Time Study; Tissue Differentiation; Tissue Sample; Tissues; Work; XCL1 gene; accurate diagnosis; alpha synuclein; base; brain cell; brain tissue; cell type; demographics; disease diagnosis; disease phenotype; genomic platform; improved; individual patient; induced pluripotent stem cell; molecular phenotype; motor impairment; multi-electrode arrays; multiple omics; neuron loss; neuronal excitability; new therapeutic target; novel; novel marker; novel therapeutics; participant enrollment; patient population; patient stratification; protein TDP-43; specific biomarkers; stem cell differentiation; stressor; symptom treatment; synaptic function; tau Proteins; tau-1; transcriptome; transcriptome sequencing; transcriptomics

PROJECT ABSTRACT Lewy Body dementia (LBD) is a spectrum disease that includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The two dementias share neuropathological characteristics of alpha- synuclein (a-syn) inclusion in so called Lewy bodies, in addition to variable pathologies related to Alzheimer’s disease – amyloid-beta (Ab) plaques and/or neurofibrillary tangles (NFT) of hyperposphorylated tau. One of the most distinct differences between PDD and DLB is the temporal occurrence of motor impairments relative to cognitive impairments. This often challenges an accurate diagnosis and consequently appropriate patient enrollment in clinical trials, patient care and existing symptomatic treatment. To better understand the distinct temporal progression of these two dementias we propose to utilize patient-derived induced pluripotent stem cell (iPSC) culture models – a disease model system that offers personalized patient analyses and drug screening. To ensure that this model system accurately reflects the individual patient’s disease pathogenesis, we propose to generate iPSCs differentiated into neurons from individuals from which we also have postmortem autopsy tissue available. This provides us with the unique opportunity to directly compare transcriptomics and disease pathology from brain tissue and differentiated iPSC-neurons from the same individual. In addition, we are able to monitor and characterize disease progression in PDD compared to DLB in a temporal manner. We hypothesize that iPSC-neurons from PDD patients will show phenotypic differences in their temporal disease progression compared to DLB patient iPSC-neurons. We further hypothesize that there are similarities of gene expression profiles and disease pathologies between differentiated iPSC-neurons and primary autopsy tissue obtained from the same individuals. To test this hypothesis we will perform single nuclei multi-omics sequencing (snRNA- and ATAC seq) from PDD, DLB and healthy control autopsy brain tissues (Aim 1). In Aim 2, we will differentiate PDD and DLB iPSCs (from the same individuals as Aim 1) into cortical forebrain neurons to generate a disease-specific neuronal transcriptome profile and to examine PD and dementia-related disease phenotypes. These studies will for the first time study the transcriptome profile of PDD and DLB, examine cellular disease phenotypes in a temporal manner and address the disease mechanisms of LBD in this spectrum disorder. Additionally, this work will provide novel opportunities for drug target identification with the hope of identifying novel therapeutics and biomarkers specific for each of the two disorders. This in return will facilitate the much- needed improvement of disease diagnosis and management of PDD and DLB patients.

项目摘要 Lewy身体痴呆（LBD）是一种谱系疾病，包括带有路易体（DLB）和的痴呆症 帕金森氏病痴呆症（PDD）。这两个痴呆具有α-具有神经病理学特征 除了与阿尔茨海默氏症相关的可变病理外，Synulein（A-Syn）包含在所谓的Lewy身体中 疾病 - 高磷酸化tau的淀粉样蛋白β（AB）斑块和/或神经纤维缠结（NFT）。中的一个 PDD和DLB之间最明显的差异是相对于运动障碍的暂时出现 认知障碍。这通常会挑战准确的诊断且因此适当的患者 参加临床试验，患者护理和现有症状治疗。更好地理解独特的 我们建议利用患者衍生的多能干细胞的这两个痴呆症的暂时进展 （IPSC）培养模型 - 一种疾病模型系统，可提供个性化的患者分析和药物筛查。 为确保该模型系统准确反映了个体患者的疾病发病机理，我们提出 为了生成IPSC，从我们的个体中分化为神经元，我们也有尸体尸检 可用的组织。这为我们提供了直接比较转录组学和疾病的独特机会 来自脑组织和IPSC神经元与同一个体的病理。此外，我们能够 与DLB相比，以临时方式监测和表征PDD中的疾病进展。我们 假设来自PDD患者的IPSC-神经元会在其临时疾病中显示表型差异 与DLB患者IPSC-神经元相比，进展。我们进一步假设基因有相似之处 分化的IPSC-神经元和原发性尸检组织之间的表达谱和疾病病理 从同一个人获得。为了检验该假设，我们将执行单核多词测序 （SNRNA和ATAC SEQ）来自PDD，DLB和健康对照尸检脑组织（AIM 1）。在AIM 2中，我们将 将PDD和DLB IPSC（从与AIM 1相同的个体）区分为皮质前脑神经元 疾病特异性的神经元转录组谱，并检查与PD和痴呆相关的疾病表型。 这些研究将首次研究PDD和DLB的转录组谱，检查细胞疾病 表型以暂时的方式解决该频谱疾病中LBD的疾病机制。 此外，这项工作将为药物靶标识别提供新的机会，以期确定 针对两种疾病中每一种的新型疗法和生物标志物。作为回报，这将有助于 需要改善PDD和DLB患者的疾病诊断和管理。