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

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病（AD）患者到CNS神经元表型的人类皮肤成纤维细胞的定向转化，称为人诱导神经元细胞（hiN） 1。在此，我们建议进一步开发hiN细胞作为AD建模的工具，并随后在更详细的AD细胞机制分析中验证该方法。拟议研究的重点是家族性AD （FAD）相关疾病，这些疾病具有早老素-1 （PSEN1）或早老素-2 （PSEN2）明确的遗传病变。对具有明确突变的FAD进行这种分析的一个明显优势是，这有助于基因“拯救”研究，以及功能的基因解剖。然而最终，也许hiN细胞技术最令人兴奋的方面是，它可能允许对“散发性”疾病进行细胞分析。在这项工作中需要测试的主要假设是FAD病理生理的细胞方面：(1)细胞自主神经元并通过表观遗传重编程维持，因此可用于hiN细胞建模。(2)包括胞内小泡运输在体细胞和突触的改变。该工作的成果包括：(1)用于阿尔茨海默病机制解剖和药物筛选的新型人类神经元细胞模型。(2)可广泛应用于神经系统疾病研究的定向重编程工具。

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.