Hypocretin and its receptors Gene Transfer for Narcolepsy

下丘脑分泌素及其受体基因转移治疗发作性睡病

• 批准号: 8548216
• 负责人: Meng Liu
• 金额: $ 12.62万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548216
• 关键词: Adverse effects; Affect; American; Amygdaloid structure; Area; Behavior; Behavioral; Biological Neural Networks; Brain; Brain region; Canis familiaris; Cataplexy; Cells; Characteristics; China; Chinese People; Clinical; Data; Data Analyses; Disease; Doctor of Medicine; Doctor of Philosophy; Excessive Daytime Sleepiness; Faculty; Fiber; Gene Delivery; Gene Transfer; Genes; Genetic; Goals; Human; Hypothalamic structure; Knockout Mice; Knowledge; Laboratories; Lateral; Learning; Link; MJD1 protein; Medical; Medical center; Medicine; Mentored Research Scientist Development Award; Methodology; Methods; Modeling; Molecular Biology; Mus; Mutation; Names; Narcolepsy; Nerve Degeneration; Neurobiology; Neurons; Neuropeptides; Neurosciences; Optics; Paper; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Phenotype; Positioning Attribute; Publishing; RRM2 gene; Receptor Gene; Regulation; Research; Research Personnel; Research Project Grants; Scientist; Secure; Site; Sleep; Sleep Disorders; Solid; South Carolina; Stem cells; Supervision; Symptoms; System; Techniques; Technology; Testing; Time; Training; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Universities; Vision; Visit; Wakefulness; Work; aged; alternative treatment; base; career; cost; gene therapy; human disease; hypocretin; instructor; locus ceruleus structure; mammilloinfundibular nucleus structure; medical schools; meetings; mouse model; nervous system disorder; neuron loss; optogenetics; orexin B receptor; professor; public health relevance; receptor; sleep regulation; success; tool; vector; zona incerta

DESCRIPTION (provided by applicant): I have had a remarkable journey. I grew up in a small town about a thousand miles north of Beijing, China. I worked my way up through the Chinese system, obtaining both M.D. and Ph.D. in the best medical university in China: Beijing Medical University. I then joined Dr. Alfred Geller's laboratory at the Harvard Medical School/VA Medical Center in 2002. After 4 years training in molecular biology and gene therapy, I joined Dr. Priyattam Shiromani's laboratory in 2006 to start a new research field: gene therapy for sleep disorders. We published the first "proof of principal" paper in narcolepsy gene transfer research area in 2008. I was promoted to instructor, a faculty level position at Harvard Medical School and also that year I received my permanent resident status. In 2011, our laboratory relocated to the Medical University of South Carolina and I was promoted to assistant professor (tenure track). I am intent on developing my academic carrier in the US. I am skilled in molecular biology and have a broad overall knowledge of neuroscience. However, for me to reach my career objectives I require additional training in sleep neurobiology, as this is a new field for m. The long-term goal of this proposal is to develop a gene therapy treatment for human narcolepsy and other sleep disorders. The short term goal is to determine the specific HCRT target areas responsible for narcoleptic symptoms, and their phenotypes. This proposal will provide training in sleep neurobiology, especially narcolepsy. Training includes basic lab work under the supervision of established scientists, course work, presentations at scientific meetings, and visiting established investigators to learn about other sleep disorders and new methods such as optogenetics. This training will enable me to become an independent scientist in sleep neuroscience and allow me to be competitive in securing an independent NIH research grant (R01). Narcolepsy is a neurodegenerative sleep disorder affecting almost 1:2000 Americans. Ten years ago the neuropeptide hypocretin (HCRT), also known as orexin, was linked to narcolepsy, and deficiency of HCRT was found to be the main reason of human narcolepsy. But it is still not known where in the brain are the key targets for HCRT. This information is necessary to identify potential therapies to reverse the narcoleptic symptoms. Current treatments of narcolepsy mainly depend on pharmacotherapy which can treat some but not all of the symptoms of narcolepsy and most of these medicines have severe side effects. Our group is pioneering in the field of Narcolepsy gene therapy. We have established that HCRT gene transfer in lateral hypothalamus (LH) or other related brain areas such as Zona Incerta can correct narcoleptic symptoms in HCRT/ataxin-3 transgenic mice, a reliable mouse model of narcolepsy. Drawing on the success of this work we are proposing this project where we will construct vectors to transfer the genes for the HCRT or its receptor into specific brain areas involved in sleep-wake regulation, or stimulate/inhibit these neurons with the optogenetic method. Our strategic intent is to use gene transfer and optogenetic tools to reverse the symptoms of narcolepsy and thereby identify the brain area that regulates sleep. We will examine if such gene transfer strategies can also correct narcoleptic symptoms in aged (2y) mice. I am the only one in sleep research conducting gene transfer studies in old mice. I believe it important to identify the phenotype of the surrogate neuron that rescues the narcoleptic behavior. Such targeted therapy is being used in other clinical disorders, and my vision is that it can also be used to treat specific symptoms of narcolepsy and other disorders of sleep and wakefulness. Results of this project will serve as a strong base for discovering better alternative treatments for human narcolepsy.

描述（由申请人提供）：我经历了一次非凡的旅程。我在中国北京以北约一千英里的一个小镇长大。我通过中国的系统一路向上，获得了医学博士和博士学位。中国最好的医科大学：北京医科大学。 2002年，我加入哈佛医学院/退伍军人管理局医学中心的Alfred Geller博士实验室。经过4年的分子生物学和基因治疗培训，我于2006年加入Priyattam Shiromani博士的实验室，开始了一个新的研究领域：睡眠障碍的基因治疗。 2008年，我们在发作性睡病基因转移研究领域发表了第一篇“校长证明”论文。我被提升为哈佛医学院的讲师和教员级别职位，同年我获得了永久居民身份。 2011年，我们的实验室搬迁到南卡罗来纳医科大学，我晋升为助理教授（终身教授）。我决心在美国发展我的学术载体。我精通分子生物学，并对神经科学拥有广泛的整体知识。然而，为了实现我的职业目标，我需要额外的睡眠神经生物学培训，因为这对我来说是一个新领域。 该提案的长期目标是开发一种针对人类嗜睡症和其他睡眠障碍的基因疗法。短期目标是确定导致发作性睡病症状及其表型的特定 HCRT 目标区域。该提案将提供睡眠神经生物学，特别是发作性睡病方面的培训。培训包括在知名科学家的监督下进行基本实验室工作、课程作业、在科学会议上的演讲，以及拜访知名研究人员以了解其他睡眠障碍和光遗传学等新方法。这项培训将使我成为睡眠神经科学领域的独立科学家，并让我在获得独立的 NIH 研究经费 (R01) 方面具有竞争力。 发作性睡病是一种神经退行性睡眠障碍，影响着近 1:2000 的美国人。十年前，神经肽下丘脑分泌素（HCRT），也称为食欲素，被认为与发作性睡病有关，并且发现 HCRT 缺乏是人类发作性睡病的主要原因。但目前尚不清楚 HCRT 的关键靶点是大脑中的哪个部位。这些信息对于确定逆转发作性睡病症状的潜在疗法是必要的。目前发作性睡病的治疗主要依靠药物治疗，药物治疗只能治疗部分但不是全部的发作性睡病症状，且大多数药物都有严重的副作用。我们的团队在嗜睡症基因治疗领域处于领先地位。我们已经确定，在下丘脑外侧 (LH) 或其他相关大脑区域（例如未确定带）中进行 HCRT 基因转移可以纠正 HCRT/ataxin-3 转基因小鼠（一种可靠的发作性睡病小鼠模型）的发作性睡病症状。借鉴这项工作的成功，我们提出了这个项目，我们将构建载体，将 HCRT 或其受体的基因转移到涉及睡眠-觉醒调节的特定大脑区域，或用光遗传学方法刺激/抑制这些神经元。我们的战略意图是利用基因转移和光遗传学工具来扭转发作性睡病的症状，从而识别调节睡眠的大脑区域。我们将研究这种基因转移策略是否也可以纠正老年（2 岁）小鼠的发作性睡病症状。我是睡眠研究领域唯一一位对老年小鼠进行基因转移研究的人。我认为识别挽救发作性睡病行为的替代神经元的表型很重要。这种靶向治疗正在用于其他临床疾病，我的愿景是它 也可用于治疗发作性睡病和其他睡眠和觉醒障碍的特定症状。该项目的结果将为发现更好的替代方案奠定坚实的基础 人类发作性睡病的治疗。