Generation of Hypocretin Neurons from Narcoleptic Patients

描述（由申请人提供）：本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。发作性睡病是一种使人衰弱的睡眠障碍，通常是由于下丘脑中产生肽神经递质下丘脑泌素（HCRT）的神经元丢失引起的。HCRT神经元变性的原因是未知的，并且难以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疾病的进展，逃避严格的体内研究。嗜睡症非常适合体外建模，因为与ALS一样，它是由特定神经元类型的特定损失引起的。在这里，我们建议从发作性睡眠受试者中产生iPS细胞，并将其分化为HCRT神经元，以便将来研究疾病机制。为了实现这一目标，希耶、Eggan、Scammell和白色实验室将在两年时间内合作，优化从ES细胞生产Hcrt神经元（目标1），并从发作性睡眠受试者生产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嗜睡症和神经变性的公共资源。 公共卫生相关性：嗜睡症是一种使人衰弱的睡眠障碍，通常是由大脑中特定神经元的丢失引起的。该项目旨在从控制和发作性睡眠患者中培养这些神经元。

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.