Disease Pluripotent Stem (iPS) Cells

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种由“运动神经元存活（SMN）”基因突变引起的进行性神经退行性疾病，导致脊髓运动神经元变性和肌肉萎缩。它是没有有效治疗的婴儿死亡的主要原因之一。该试点提案旨在使用SMA患者的皮肤细胞创建SMA的细胞模型。具体来说，我们将首先使用最近建立的方法，通过表达多能转录因子，从SMA患者的成纤维细胞中诱导多能干细胞（iPS）。然后，我们将使用我们为人类胚胎干细胞建立的可重复分化方案，指导SMA-iPS细胞以及非SMA-iPS细胞和人类胚胎干细胞（NIH注册：WA07和WA09）向脊髓运动神经元分化。我们将确定SMA-iPS细胞衍生的运动神经元的发育（分化、神经突延伸）和功能（轴突运输、与肌肉的相互作用）是否存在缺陷。因此，我们将首次创造sma特异性的人类iPS细胞，这将允许在人类遗传背景下研究脊髓运动神经元变性的发病机制。该系统也可以作为一个简单但真正的人类SMA治疗筛选的靶点，这是我们的主要目标。

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease caused by mutations in the "survival of motor neuron (SMN)" gene, leading to spinal motor neuron degeneration and muscular atrophy. It is one of the leading causes of infant death without an effective treatment. This pilot proposal intends to create a cellular model of SMA using SMA patient's skin cells. Specifically, we will first induce pluripotent stem (iPS) cells from an SMA patient's fibroblasts by expressing pluripotent transcription factors using a recently established method. We will then direct the SMA-iPS cells, alongside non-SMA iPS cells and human embryonic stem cells (NIH Registry: WA07 and WA09), toward spinal motor neurons using our reproducible differentiation protocol established for human embryonic stem cells. We will determine if the development (differentiation, neurite extension) and function (axonal transportation, interactions with muscles) of motor neurons derived from the SMA-iPS cells are defective. Thus, we will create for the first time SMA-specific human iPS cells, which will permit studies on the pathogenesis of spinal motor neuron degeneration under the human genetic background. This system can also serve as a simple but bona fide human SMA target for therapeutic screening, our main goal. PUBLIC HEALTH RELEVANCE: We are building stem cells from the skin cells of patients with spinal muscular atrophy (SMA). The stem cells will offer a model system to study the pathogenesis of spinal motor neuron degeneration under the human genetic background. It can also serve as a simple but bona fide human SMA target for therapeutic screening, which may ultimately lead to the discovery of a treatment for SMA.