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: 8383048
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383048
• 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; 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. PUBLIC HEALTH RELEVANCE: We will develop a gene delivery method to transfer specific genes for the hypocretin or its receptor into hypocretin/ataxin-3 transgenic or HCRT receptor-null mice. Such a "genetic pharmacology" method, combined with the newest optogenetic technique, represents a neurobiological tool to understand the neural networking underlying narcolepsy, a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide hypocretin, also named orexin. Results of this project will serve as a strong base for discovering better alternative treatments for human narcolepsy. This proposal will work as a solid bridge towards becoming an independent investigator in sleep neurobiology and other neurological diseases.

描述（由申请人提供）：我经历了一段不平凡的旅程。我在中国北京以北一千英里的一个小镇上长大。我在中国的教育体系中一路高升，在中国最好的医科大学——北京医科大学获得了医学博士和博士学位。2002年，我加入了哈佛医学院/退伍军人医疗中心阿尔弗雷德·盖勒博士的实验室。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，我们在嗜睡症基因转移研究领域发表了第一篇“principal proof”论文。我被提升为讲师，哈佛医学院的教员级别职位，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，我被提升为助理教授（终身教职）。我打算在美国发展我的学术载体。我精通分子生物学，对神经科学有广泛的全面了解。然而，为了实现我的职业目标，我需要在睡眠神经生物学方面进行额外的培训，因为这对我来说是一个新的领域。本提案的长期目标是开发一种治疗人类嗜睡症和其他睡眠障碍的基因疗法。短期目标是确定负责发作性睡症症状的特定HCRT靶区及其表型。这一提议将提供睡眠神经生物学方面的培训，尤其是嗜睡症。培训包括在知名科学家的监督下进行基本的实验室工作、课程作业、在科学会议上发表演讲，以及访问知名研究人员以了解其他睡眠障碍和光遗传学等新方法。这一培训将使我成为一名独立的睡眠神经科学科学家，并使我有竞争力获得独立的NIH研究资助（R01）。嗜睡症是一种神经退行性睡眠障碍，影响了近1 / 2000的美国人。十年前，神经肽下丘脑分泌素（HCRT），也被称为食欲素，与嗜睡症有关，HCRT的缺乏被发现是人类嗜睡症的主要原因。但目前仍不清楚HCRT在大脑的哪个部位是关键靶点。这些信息对于确定逆转发作性睡症症状的潜在疗法是必要的。目前对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发作性睡病症状，但不能治疗全部症状，而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。我们已经证实，HCRT基因在侧下丘脑（LH）或其他相关脑区（如Incerta）转移可以纠正HCRT/ataxin-3转基因小鼠的发作性睡症症状，这是一种可靠的小鼠发作性睡症模型。利用这项工作的成功，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参与睡眠-觉醒调节的特定大脑区域，或者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逆转发作性睡病的症状，从而确定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）小鼠的发作性睡症症状。我是睡眠研究领域唯一一个在年老老鼠身上进行基因转移研究的人。我认为重要的是确定替代神经元的表型，挽救发作性睡症的行为。这种靶向治疗被用于其他临床疾病，我的愿景是