Sleepiness and sleep drunkenness: narcolepsy versus GABA-related hypersomnia

描述（由申请人提供）：本申请详细说明了职业发展计划和研究项目，旨在发展林恩玛丽特罗蒂，医学博士，理学硕士，成为一个独立的临床研究人员专门从事评估和治疗嗜睡，特别是在中枢神经系统嗜睡的经验。这一建议建立在令人兴奋的最新发现的基础上，她帮助实现了在嗜睡症患者的脑脊液中GABA-A受体的内源性正变构调节剂。该提案利用了她在临床研究方面的教育和睡眠医学领域的早期科学努力，是获得必要培训和经验的下一步，以建立她作为独立临床医生-科学家的成功职业生涯。她的指导团队将由医学博士大卫·拉伊组成，博士（睡眠神经学），Carolyn Meltzer，医学博士（放射学），胡小平博士（生物医学工程），布鲁斯克罗森博士（神经病学）和Helen Mayberg，医学博士，博士（神经病学/精神病学/放射学）。这些杰出的科学家为这个项目带来了互补的经验和专业知识。所有导师都有成功指导学员和初级教师的悠久历史。这项工作将在埃默里大学进行，该大学为Trotti博士的短期和长期职业发展以及本研究项目的表现提供了无与伦比的环境。Trotti博士的最终目标是将关于嗜睡的病理生理学的发现转化为对这种致残症状的更有效的治疗方法。作为实现这一长期目标的下一步，她在资助期间有三个立即计划：1）精通设计，收集， 2）发展和培养与导师及其他神经病学和功能性神经影像学领域专家的合作关系; 3）获得临床研究的实践经验和宝贵的研究数据，使她能够过渡到独立的研究生涯。为了实现这些目标，Trotti博士将接受功能性神经成像模式，PET和MRI数据解释以及应用线性模型的正式课程。她将接受实践培训，并在成像处理，分析和解释的经验。她将经常与她的经验丰富，有成就的导师团队举行正式会议，以学习他们在临床研究方面的丰富经验。 Trotti博士的研究方案将最近在大多数CNS睡眠过度患者中发现的过量GABA-A受体增强转化为关于嗜睡的病理学的重要问题，即：1）功能性神经成像是否证实了GABA能网络在患有这种形式的睡眠过度的患者中的嗜睡中的作用，与在其他睡眠过度患者中所见的不同（即，下丘脑泌素缺乏型发作性睡病患者）; 2）大脑默认模式网络内的连接改变是否与嗜睡症患者的嗜睡相关; 3）睡眠醉酒（从睡眠到清醒过渡严重困难的症状）是否反映了持续到清醒的功能连接改变？这些问题的解决将是GABA相关嗜睡症患者的一个重要进展，但也将为病理性日间嗜睡这一更广泛和常见的问题提供见解。这项研究和培训计划的成功完成也将为Trotti博士的独立临床研究生涯奠定科学基础， 运用神经影像学技术来促进对困倦的理解和治疗。

DESCRIPTION (provided by applicant): This application details the career development plan and research project designed to develop Lynn Marie Trotti, M.D., M.Sc., into an independent clinical researcher specializing in the evaluation and treatment of sleepiness, in particular that experienced in the central nervous system hypersomnia's. This proposal builds upon the exciting recent discovery that she helped to realize of an endogenous, positive allosteric modulator of the GABA-A receptor in the cerebrospinal fluid of hypersomnia patients. The proposal makes use of her education in Clinical Research and early scientific efforts in the field of sleep medicine, and is the next step in gaining the necessary training and experience to establish her successful career as an independent clinician- scientist. Her mentoring team will consist of David Rye, M.D., Ph.D. (Sleep Neurology), Carolyn Meltzer, M.D. (Radiology), Xiaoping Hu, Ph.D. (Biomedical Engineering), Bruce Crosson, Ph.D. (Neurology), and Helen Mayberg, M.D., Ph.D. (Neurology/Psychiatry/Radiology). These outstanding scientists bring complementary experience and expertise to this project. All mentors have long histories of successful mentoring of trainees and junior faculty. This work will take place at Emory University, which features an unrivaled environment for the short- and long-term career development of Dr. Trotti and for the performance of this research project. Dr. Trotti's ultimate goal is to translate discoveries regarding the pathophysiology of sleepiness into more effective treatments for this disabling symptom. As the next step in reaching this long-term goal, she has three immediate plans for this grant period: 1) to become proficient in the design, collection, and analysis of functional neuroimaging studies; 2) to develop and foster collaborative relationships with her mentors and other experts in the fields of neurology and functional neuroimaging; and 3) to gain hands-on experience in clinical research and valuable research data to allow her to transition to an independent research career. To reach these goals, Dr. Trotti will receive formal coursework in functional neuroimaging modalities, interpretation of PET and MRI data, and applied linear models. She will receive hands-on training and experience in imaging processing, analysis, and interpretation. She will have frequent, formal meetings with her team of experienced, accomplished mentors to learn from their wealth of experience in clinical research. Dr. Trotti's research protocol translates the recent discovery of excess GABA-A receptor potentiation in the majority of CNS hypersomnia patients into important questions regarding the symptomatology of sleepiness, namely: 1) does functional neuroimaging confirm a role of GABA-ergic networks in sleepiness in patients with this form of hypersomnia, distinct from that seen in other hypersomnia patients (i.e., those with hypocretin-deficient narcolepsy); 2) does altered connectivity within the brain's default mode network correlate with sleepiness in hypersomnia patients; and 3) does sleep drunkenness, the symptom of severe difficulty in transitioning from sleep to wake, reflect altered functional connectivity persisting into wakefulness? Answering these questions will be an important advance for those with GABA-related hypersomnia, but will also provide insights into the broader and common problem of pathological daytime sleepiness. The successful completion of this research and training plan will also serve as the scientific groundwork for Dr. Trotti's independent clinical research career, applying neuroimaging techniques to advance the understanding and treatment of sleepiness.