Generation of Hypocretin Neurons from Narcoleptic Patients

项目描述（由申请人提供）：该项目的目标是产生一种新的资源来研究人类神经系统疾病嗜睡症。嗜睡症是一种使人衰弱的睡眠障碍，通常是由下丘脑中产生肽神经递质下丘脑分泌素（HCRT）的神经元丧失引起的。HCRT神经元变性的原因尚不清楚，并且很难用现有技术来研究。随着诱导多能干细胞（iPS）技术的出现，现在有可能在体外研究无法在体内进行严格研究的疾病的进展。发作性睡病非常适合体外建模，因为像ALS一样，它是由特定神经元类型的特定损失引起的。在此，我们建议从发作性睡症受试者中生成iPS细胞，并将其分化为HCRT神经元，以便进一步研究疾病机制。为了实现这一目标，Schier、Eggan、Scammell和White实验室将在两年的时间内合作，优化从ES细胞（目标1）中产生Hcrt神经元，并从发作性睡症受试者中产生iPS细胞和Hcrt神经元（目标2）。由此产生的患者特异性细胞将作为研究发作性睡病和神经变性的公共资源。

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.