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）：我们最近描述了从未受影响的个体和阿尔茨海默氏病（AD）患者（AD）患者到CNS神经元表型的人皮肤成纤维细胞的定向转化，称为人类诱导的神经元细胞（HIN）1。在此，我们建议在用于验证AD详细分析的方法中，以进一步开发HIN细胞，以进一步开发HIN细胞，以进行详细的分析。拟议的研究的重点是在Presenilin-1（PSEN1）或Presenilin-2（PSEN2）中与定义的遗传病变的家族性AD（FAD）相关疾病（PSEN2）。对使用定义的突变进行这种FAD的这种明确优势是，这促进了遗传“救援”研究以及功能的遗传解剖。然而，最终，HIN细胞技术中最令人兴奋的方面可能是它可以允许对“零星”疾病进行细胞分析。在这项工作中要检验的总体假设是FAD病理生理学的细胞方面是：（1）神经元细胞自主，并通过表观遗传重编程维持，因此可以适合HIN细胞建模。 （2）包括改变体内的细胞内囊泡贩运和突触。提出的这项工作的拟议可交付成果是：（1）新型的人类神经元细胞模型，用于解剖AD机制和药物筛查。 （2）可以广泛应用于神经系统疾病的定向重编程工具。 公共卫生相关性：我们通过人类皮细胞的定向转换来描述一种新的人类神经元的方法。当这种神经元源自具有家族形式的阿尔茨海默氏症患者时，会显示出代表该疾病的病理变化。在这里，我们建议研究人类阿尔茨海默氏症患者神经元出现细胞和分子缺陷的机制。