Loss of nuclear integrity is sufficient to induce age-associated changes and Alzheimer's pathology in hPSC-derived cortical neurons.

核完整性的丧失足以在 hPSC 衍生的皮质神经元中诱发与年龄相关的变化和阿尔茨海默病病理。

• 批准号: 10405026
• 负责人: Andrew Minotti
• 金额: $ 4.68万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-13 至 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405026
• 关键词: Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Biochemical; Biological Assay; Brain; Carrier Proteins; Cause of Death; Cell Aging; Cell Death; Cell Nucleus; Cell model; Cells; Chemosensitization; Complex; DNA Damage; DNA Sequence Alteration; Degenerative Disorder; Developed Countries; Disease; Disease model; Drug Screening; Elderly; Electrophysiology (science); Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Flow Cytometry; Genetic; Genetic Diseases; Genetic Risk; Genetic study; Guanosine Triphosphate Phosphohydrolases; Healthcare; Heterochromatin; Homeostasis; Human; Immunofluorescence Immunologic; Impairment; International; Knock-out; LMNB1 gene; Lamins; Late-Onset Disorder; Link; Measures; Membrane; Methods; Modeling; Molecular; Mutation; Neurites; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Nuclear Envelope; Nuclear Lamina; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Parkinson Disease; Pathologic; Patients; Phenotype; Population; Premature aging syndrome; Process; Progeria; Proteins; Protocols documentation; Reactive Oxygen Species; Regulation; Research Project Grants; Resolution; Risk Factors; Senile Plaques; Signal Transduction; Somatic Cell; Stress; Synapses; Syndrome; System; Techniques; Tissues; United States; age related; aged; amyloid precursor protein processing; base; cell type; differential expression; disease phenotype; experimental study; genetic approach; high risk; human embryonic stem cell; induced pluripotent stem cell; innovation; insight; mitochondrial dysfunction; multi-electrode arrays; neuron loss; novel; novel strategies; nucleocytoplasmic transport; overexpression; prenatal; proteostasis; stem cell model; tau aggregation; tau phosphorylation

Project Abstract: Alzheimer’s Disease (AD) is the most common neurodegenerative disease in the United States affecting an estimated 5.4 million patients 48. To date, there are no effective cures and limited therapies available for patients 49. While a small number of AD cases are linked to genetic mutations in Amyloid Precursor Protein processing, the genetic basis of most AD cases remains poorly understood 50. Induce Pluripotent Stem Cells (iPSCs) provide a unique opportunity to study the genetics of AD, by providing an unlimited supply of disease- relevant tissue while retaining the genetic background of their somatic cell donor 51. Studies have shown the process of iPSC reprogramming resets the age of patient iPSCs 5. Consequently, cells derived from iPSCs tend to yield immature and prenatal cell types, presenting a major hurdle for late-onset disease modelling 5, 6. Induced aging protocols are a novel strategy for accelerating age in iPSC-derived cells for modelling late-stage degenerative disease phenotypes 5,6. While these protocols have been established for generating iPSC-based models of Parkinson’s Disease, they have yet to be applied to AD. There are numerous studies which describe a decline in multiple aspects of nuclear homeostasis that occur with age and in AD patient brains, including differential expression of lamin proteins, a shift in nuclear-cytoplasmic transport activity, and a decline in nucleoporin and transport proteins 8-10, 22, 24, 25, 35-38. It is therefore plausible that a loss of nuclear integrity is sufficient to induce age-related and pathological changes associated with AD in hPSC-derived cortical neurons. The proposed research project aims to use genetic strategies to mimic age-associated changes within the nucleus to determine if nuclear perturbation is sufficient to drive other aspects of cellular age and potentiate AD pathology. These studies could create an innovative age-implicated model of AD, develop novel methods for modelling late-onset diseases in other cell types, and provide new insights into drivers of cellular and nuclear aging.

项目摘要： 阿尔茨海默病（AD）是美国最常见的神经退行性疾病， 估计有540万名患者48.到目前为止，没有有效的治愈方法和有限的治疗方法， 病人49.虽然少数AD病例与淀粉样前体蛋白基因突变有关， 尽管在基因治疗过程中，大多数AD病例的遗传基础仍然知之甚少50。诱导多能干细胞 多能干细胞（iPSCs）通过提供无限的疾病供应，为研究AD的遗传学提供了一个独特的机会， 相关组织，同时保留其体细胞供体51的遗传背景。研究显示 iPSC重编程的过程重置患者iPSC的年龄5.因此，来自iPSC的细胞倾向于 产生不成熟和产前细胞类型，为迟发性疾病建模提出了一个主要障碍5，6。诱导 衰老方案是一种加速iPSC衍生细胞衰老的新策略， 退行性疾病表型5，6.虽然已经建立了这些方案用于产生基于iPSC的细胞， 帕金森病的模型，他们还没有被应用到AD。有许多研究描述了 随着年龄的增长和AD患者大脑中发生的核稳态的多个方面的下降，包括 核纤层蛋白质的差异表达，核质转运活性的转变，以及核纤层蛋白表达的下降。 核孔蛋白和转运蛋白8-10，22，24，25，35-38。因此，核完整性的丧失似乎是合理的。 足以在hPSC衍生的皮质神经元中诱导与AD相关的年龄相关的和病理学变化。 拟议中的研究项目旨在利用遗传策略来模拟与年龄相关的变化， 核以确定核扰动是否足以驱动细胞年龄的其他方面并增强AD 病理这些研究可以创造一个创新的年龄相关的AD模型，开发新的方法， 在其他细胞类型中模拟迟发性疾病，并为细胞和核的驱动因素提供新的见解。 衰老