Generation of Hypocretin Neurons from Narcoleptic Patients

描述(申请人提供)：这个项目的目标是产生一种新的资源来研究人类神经疾病发作性睡病。发作性睡病是一种衰弱的睡眠障碍，通常由下丘脑产生多肽神经递质下丘脑(HCRT)的神经元丢失引起。HCRT神经元变性的原因尚不清楚，很难使用现有技术进行研究。随着诱导多能干细胞(IPS)技术的出现，现在可以在体外研究那些未能在体内进行严格研究的疾病的进展。发作性睡病非常适合于体外建模，因为像ALS一样，它是由特定的特定神经元类型的丧失引起的。在这里，我们建议从发作性睡病患者中培养iPS细胞，并将其分化为HCRT神经元，以便将来对疾病机制的研究。为了实现这一目标，Schier、Eggan、Scammell和White实验室将在两年内合作，优化ES细胞产生Hcrt神经元(目标1)，并从发作性睡病患者产生iPS细胞和HCRT神经元(目标2)。由此产生的针对患者的细胞将成为研究发作性睡病和神经退行性变的公共资源。 与公共健康相关：嗜睡症是一种衰弱的睡眠障碍，通常由大脑中特定神经元的丧失引起。该项目旨在从对照组和发作性睡病患者的培养中产生这些神经元。

DESCRIPTION (provided by applicant): The goal of this project is to generate a novel resource to study the human neurological disease narcolepsy. Narcolepsy is a debilitating sleep disorder that is often caused by the loss of neurons in the hypothalamus that produce the peptide neurotransmitter hypocretin (HCRT). The cause of HCRT neuron degeneration is unknown and has been difficult to study using existing techniques. With the advent of induced pluripotent stem (iPS) cell technology it is now possible to study in vitro the progression of diseases that have eluded rigorous study in vivo. Narcolepsy is ideally suited for in vitro modeling since, like ALS, it is caused by the specific loss of a defined neuron type. Here we propose to generate iPS cells from narcoleptic subjects and differentiate them into HCRT neurons in order to allow the future study of disease mechanisms. To achieve this goal, the Schier, Eggan, Scammell and White labs will collaborate over a two-year period to optimize the production of Hcrt neurons from ES cells (Aim 1) and produce iPS cells and HCRT neurons from narcoleptic subjects (Aim 2). The resulting patient-specific cells will serve as a public resource to study narcolepsy and neurodegeneration. PUBLIC HEALTH RELEVANCE: Narcolepsy is a debilitating sleep disorder that is often caused by the loss of specific neurons in the brain. This project aims to generate these neurons in culture from control and narcoleptic patients.