iPSC Modeling of AD Using Progerin

使用 Progerin 对 AD 进行 iPSC 建模

基本信息

批准号：
10153610
负责人：
SALLY TEMPLE
金额：
$ 40.31万
依托单位：
REGENERATIVE RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153610
关键词：
3-Dimensional Address Advanced Development Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Astrocytes Autopsy Biological Assay Biology Bioreactors Cell Culture Techniques Cell Differentiation process Cell Line Cell model Cells Characteristics Chromatin Clinical Coculture Techniques Collection DNA Damage Disease Disease Progression Dopaminergic Cell Drosophila genus Ectopic Expression Enzymes Functional disorder Gene Expression Genes Goals Heterochromatin Human Impairment Individual Inherited Kinetics Lamin Type A Lamins Lasers Lead Measures Memory impairment Midbrain structure Modeling Morphology Mutation Neurites Neurons Nuclear Envelope Nuclear Lamina Onset of illness Organoids Parkinson Disease Pathogenesis Pathology Patients Phenotype Progeria Prosencephalon Protein Isoforms Proteins Stable Isotope Labeling Synapses Syndrome System Tauopathies Therapeutic Transcript Validation age related base brain cell brain tissue design disease phenotype env Gene Products extracellular in vitro Model induced pluripotent stem cell neuronal survival novel prelamin A presenilin-1 proteostasis stem cell differentiation stem cell model synaptogenesis tau Proteins tau aggregation tau-1

3-Dimensional Address Advanced Development Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Astrocytes Autopsy Biological Assay Biology Bioreactors Cell Culture Techniques Cell Differentiation process Cell Line Cell model Cells Characteristics Chromatin Clinical Coculture Techniques Collection DNA Damage Disease Disease Progression Dopaminergic Cell Drosophila genus Ectopic Expression Enzymes Functional disorder Gene Expression Genes Goals Heterochromatin Human Impairment Individual Inherited Kinetics Lamin Type A Lamins Lasers Lead Measures Memory impairment Midbrain structure Modeling Morphology Mutation Neurites Neurons Nuclear Envelope Nuclear Lamina Onset of illness Organoids Parkinson Disease Pathogenesis Pathology Patients Phenotype Progeria Prosencephalon Protein Isoforms Proteins Stable Isotope Labeling Synapses Syndrome System Tauopathies Therapeutic Transcript Validation age related base brain cell brain tissue design disease phenotype env Gene Products extracellular in vitro Model induced pluripotent stem cell neuronal survival novel prelamin A presenilin-1 proteostasis stem cell differentiation stem cell model synaptogenesis tau Proteins tau aggregation tau-1

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项目摘要

Project Summary/Abstract Age is the strongest risk factor for Alzheimer's disease (AD). However, cell and animal models of AD fail to recapitulate human aging and fail to capture key aspects of disease pathology. Our long-term goal is to understand how aging contributes to AD pathogenesis. Therefore, we propose to develop an induced pluripotent stem cell (iPSC)-based model of AD that incorporates accelerated aging, with the objective of more robustly modeling AD onset and progression. Recent findings indicate that perturbations in lamin A biology may contribute to AD. In preliminary studies, we have found a significant increase in LMNA, the gene that encodes the nuclear envelope protein lamin A, and a significant decrease in ZMPSTE24, a prelamin A processing enzyme, in autopsy-confirmed AD brain tissue and in laser-dissected neurons from AD brains compared to age-matched controls. We predict that these changes in LMNA and ZMPSTE24 levels would cause an increase in farnesylated prelamin A, which has been shown to drive accelerated aging phenotypes, including acquisition of an abnormal nuclear lamina, and impairments in nucleocytoplasic compartmentation, chromatin organization and gene expression similar to the accumulation of the LMNA isoform progerin. We hypothesize that forced expression of prelamin A or progerin accelerates age-associated changes and disease phenotypes in iPSC-cortical cells derived from AD patients. First, we will determine whether lamin A expression and processing are perturbed in AD brains and AD-predisposed iPSC-cortical cells. We will then determine whether forced progerin expression causes aging-related dysfunction in AD-predisposed iPSC- cortical neurons and astrocytes. Finally, we will define and quantify the effects of forced progerin expression on cell phenotypes related to AD pathology, including Aβ and tau secretion, aggregation and turnover, in iPSC-2D cortical cells and in 3D forebrain organoids. The results from this study will determine whether perturbations in lamin A biology are associated with AD, and potentially contribute to AD pathogenesis, and will establish a novel model incorporating lamin A-related aging parameters in a human AD iPSC-cortical cell model. These findings will open novel avenues for investigating the contribution of aging to the disease mechanisms underlying AD pathology and will advance the development of in vitro models of AD to aid in the design and validation of potential therapeutic strategies.

项目摘要/摘要年龄是阿尔茨海默氏病（AD）的强大危险因素。但是，AD的细胞和动物模型无法概括人类衰老，无法捕获疾病病理学的关键方面。我们的长期目标是了解衰老如何有助于AD发病机理。因此，我们建议开发一个诱发的多能干细胞（IPSC）基于AD的模型，该模型融合了加速衰老，目的是更多稳健地对AD发作和进展进行建模。最近的发现表明层粘连蛋白A生物学的扰动可能有助于广告。在初步研究中，我们发现LMNA显着增加，该基因是编码核包膜蛋白层粘连蛋白A，并在ZMPSTE24中显着下降加工酶，在尸检确认的AD脑组织和AD大脑的激光滴神经元中与年龄匹配的对照相比。我们预测LMNA和ZMPSTE24水平的这些变化将导致Farnesytrated预序A的增加，已显示出驱动加速的衰老表型，包括获取异常核薄片，以及核圆柱隔室的损害，染色质组织和基因表达与LMNA同工蛋白的积累相似。我们假设强迫表达预胺A或启动蛋白会加速与年龄相关的变化和疾病来自AD患者的IPSC-Cortical细胞中的表型。首先，我们将确定是否层层表达和加工在AD大脑和AD鉴定的IPSC-Cortical细胞中受到干扰。然后我们会确定强迫过程表达是否引起与AD鉴定的IPSC-的衰老相关功能障碍皮质神经元和星形胶质细胞。最后，我们将定义和量化强制孕激素表达对 IPSC-2D中与AD病理学有关的细胞表型，包括Aβ和TAU分泌，聚集和周转皮质细胞和3D前脑器官。这项研究的结果将决定是否扰动层粘连蛋白A与AD有关，并有可能导致AD发病机理，并将建立一个新型模型在人AD IPSC-Cortical细胞模型中结合了层粘连蛋白A相关的衰老参数。这些调查结果将为研究衰老对疾病机制的贡献开辟新的途径基本的AD病理学，并将推进AD体外模型的发展，以帮助设计和验证潜在的治疗策略。