Human induced neuronal stem cell models of familial Alzheimer's disease

人类诱导的家族性阿尔茨海默病神经元干细胞模型

• 批准号: 8418236
• 负责人: Asa Abeliovich
• 金额: $ 51.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418236
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Back; Calcium; Cell model; Cells; Complex; Coupled; Degradation Pathway; Disease; Dissection; Early Endosome; Endocytosis; Endosomes; Epigenetic Process; Fibroblasts; Functional disorder; Generations; Genetic; Golgi Apparatus; Human; Image; Individual; Lesion; Link; Molecular; Morphology; Mutation; Neurons; Pathway interactions; Patients; Phenotype; Physiological; Play; Preclinical Drug Evaluation; Presenile Alzheimer Dementia; Property; Proteins; Role; Skin; Sorting - Cell Movement; Stem cells; Structure; Synapses; Synaptic Vesicles; Technology; Testing; Work; amyloid precursor protein processing; chemical genetics; familial Alzheimer disease; genetic variant; interest; mutant; nervous system disorder; neuronal cell body; novel; novel strategies; patch clamp; presenilin-1; presenilin-2; presynaptic; receptor; secretase; synaptic function; tool; trafficking; voltage

DESCRIPTION (provided by applicant): We recently described the directed conversion of human skin fibroblasts from unaffected individuals and Alzheimer's disease (AD) patients to a CNS neuron phenotype, termed human induced neuronal cells (hiN) 1. Herein we propose to further develop hiN cells as tools for AD modeling, and subsequently to validate the approach in a more detailed analysis of cellular mechanisms of AD. The focus of the proposed studies is on familial AD (FAD)-associated disease with defined genetic lesions in presenilin-1 (PSEN1) or presenilin-2 (PSEN2). A clear advantage of such an analysis of FAD with defined mutations is that this facilitates genetic 'rescue' studies, as well as genetic dissection of function. Yet ultimately, perhaps the most exciting aspect of the hiN cell technology is that it may permit a cellular analysis of 'sporadic' disease. The overarching hypotheses to be tested in this work are that cellular aspects of FAD pathophysiology are: (1) Cell-autonomous to neurons and maintained through epigenetic reprogramming, and therefore amenable to hiN cell modeling. (2) Include altered intracellular vesicular trafficking at the soma and the synapse. The proposed deliverables for this proposed work are: (1) Novel human neuronal cell models for dissection of AD mechanisms and drug screening. (2) Directed reprogramming tools that may be broadly applied to the study of neurological disease. PUBLIC HEALTH RELEVANCE: We describe a novel approach to the generation of human neurons by the directed conversion of human skin cells. Such neurons, when derived from patients with familial forms of Alzheimer's, show pathological changes that typify the disease. Here we propose to investigate the mechanism by which human Alzheimer patient neurons develop cellular and molecular deficits.

描述（由申请人提供）：我们最近描述了来自未受影响个体和阿尔茨海默病 (AD) 患者的人类皮肤成纤维细胞定向转化为 CNS 神经元表型，称为人类诱导神经元细胞 (hiN) 1。在此，我们建议进一步开发 hiN细胞作为 AD 建模的工具，随后在更详细的 AD 细胞机制分析中验证该方法。拟议研究的重点是早老素-1 (PSEN1) 或早老素-2 (PSEN2) 中具有明确遗传病变的家族性 AD (FAD) 相关疾病。对具有明确突变的 FAD 进行此类分析的一个明显优势是，这有助于遗传“拯救”研究以及功能的遗传剖析。然而最终，hiN 细胞技术最令人兴奋的方面也许是它可以对“散发性”疾病进行细胞分析。这项工作要测试的首要假设是 FAD 病理生理学的细胞方面是：（1）细胞对神经元具有自主性，并通过表观遗传重编程维持，因此适合 hiN 细胞建模。 (2) 包括胞体和突触处细胞内囊泡运输的改变。这项拟议工作的拟议交付成果是：（1）用于剖析 AD 机制和药物筛选的新型人类神经元细胞模型。 (2)可能广泛应用于神经系统疾病研究的定向重编程工具。 公共健康相关性：我们描述了一种通过人类皮肤细胞的定向转化来生成人类神经元的新方法。当这些神经元来自患有家族性阿尔茨海默氏症的患者时，会表现出该疾病的典型病理变化。在这里，我们建议研究人类阿尔茨海默病患者神经元产生细胞和分子缺陷的机制。