Generation of Hypocretin Neurons from Narcoleptic Patients

发作性睡病患者的下丘脑分泌素神经元的产生

• 批准号: 7993903
• 负责人: ALEXANDER F SCHIER
• 金额: $ 21万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993903
• 关键词: Affect; American; Amyotrophic Lateral Sclerosis; Biological Assay; Biopsy; Brain; Cells; Chronic; Communities; Disease; Disease Progression; Disease model; Embryo; Ensure; Exogenous Factors; Fibroblasts; Figs - dietary; Future; Generations; Genetic; Genomics; Goals; Human; Hypothalamic structure; In Vitro; Laboratories; Life; Motor Neurons; Mus; Narcolepsy; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Patients; Peptides; Physiological; Production; Protocols documentation; Resources; Signal Pathway; Skin; Sleep Disorders; Symptoms; Techniques; Work; disease mechanisms study; embryonic stem cell; human embryonic stem cell; human subject; hypocretin; in vitro Model; in vivo; induced pluripotent stem cell; morphogens; nervous system disorder; neuron loss; novel; orexin B; progenitor; public health relevance; stem; stem cell technology

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.

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发作性睡病。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分泌素 (HCRT) 的神经元缺失引起的。 HCRT 神经元变性的原因尚不清楚，并且很难使用现有技术进行研究。随着诱导多能干（iPS）细胞技术的出现，现在可以在体外研究那些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病受试者中产生 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，Schier、Eggan、Scammell 和 White 实验室将在两年内合作，优化 ES 细胞中 Hcrt 神经元的生产（目标 1），并从发作性睡病受试者中生产 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发作性睡病和神经退行性疾病的公共资源。 公共卫生相关性：发作性睡病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丧失引起的。该项目旨在从对照组和发作性睡病患者的培养物中产生这些神经元。