Hypocretin and its receptors Gene Transfer for Narcolepsy

描述(申请人提供)：我经历了一段不平凡的旅程。我在北京以北一千英里的一个小镇上长大，名叫中国。我在中国的医疗体系中一路向上，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，我加入了阿尔弗雷德·盖勒博士在哈佛医学院/退伍军人医学中心的实验室。在接受了四年的分子生物学和基因治疗培训后，我于2006年加入了Priyattam Shiroomi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。我们于2008年在发作性睡病基因转移研究领域发表了第一篇《原则证明》论文。我被提升为讲师，哈佛医学院的教员级别的职位，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)。我决心在美国发展我的学术载体。我精通分子生物学，对神经科学有全面的了解。然而，为了实现我的职业目标，我需要接受额外的睡眠神经生物学培训，因为这对m来说是一个新领域。这项提议的长期目标是开发一种治疗人类发作性睡病和其他睡眠障碍的基因疗法。短期目标是确定引起发作性睡病症状的特定HCRT靶区及其表型。这项提议将提供睡眠神经生物学方面的培训，特别是发作性睡病。培训包括在老牌科学家的监督下进行基本的实验室工作，课程工作，在科学会议上发表演讲，以及拜访老牌研究人员以了解其他睡眠障碍和光遗传学等新方法。这次培训将使我成为一名睡眠神经科学的独立科学家，并使我在获得NIH独立研究基金方面具有竞争力(R01)。嗜睡症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，神经肽下丘脑素(HCRT)，也被称为增食欲素，被认为与发作性睡病有关，而hcrt缺乏被发现是人类发作性睡病的主要原因。但目前还不清楚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。目前对发作性睡病的治疗主要依赖于药物治疗，这种疗法可以治疗部分但不是所有的发作性睡病症状，而且大多数药物都有严重的副作用。我们小组是发作性睡病基因治疗领域的先驱。我们已经证实，将HCRT基因转移到下丘脑外侧区或其他相关脑区，如疑似带，可以纠正HCRT/ataxin-3转基因小鼠的发作性睡病症状，这是一种可靠的发作性睡病小鼠模型。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参与睡眠-觉醒调节的特定脑区，或用光遗传方法刺激/抑制这些神经元。我们的战略意图是使用基因转移和光遗传工具来逆转发作性睡病的症状，从而确定大脑中调节睡眠的区域。我们将检验这种基因转移策略是否也能纠正老年(2岁)小鼠的发作性睡病症状。我是睡眠研究中唯一一个在老年小鼠身上进行基因转移研究的人。我认为重要的是确定拯救发作性睡病行为的代理神经元的表型。这种靶向治疗正被用于其他临床疾病，我的愿景是 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。

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.