Sleepiness and sleep drunkenness: narcolepsy versus GABA-related hypersomnia

嗜睡和睡眠醉酒：发作性睡病与 GABA 相关的嗜睡症

• 批准号: 8896081
• 负责人: Lynn Marie Trotti
• 金额: $ 18.18万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896081
• 关键词: Accidents; Anisotropy; Anterior; Back; Biology; Biomedical Engineering; Brain; Brain Stem; Brain imaging; Cataplexy; Cells; Cerebrospinal Fluid; Chemicals; Chemosensitization; Clinical; Clinical Research; Collection; Conscious; Data; Development Plans; Diffusion Magnetic Resonance Imaging; Disease; Doctor of Medicine; Doctor of Philosophy; Education; Environment; Etiology; Evaluation; Exhibits; Faculty; Failure; Fostering; Functional disorder; GABA-A Receptor; Goals; Grant; Health; Health Care Costs; Hyperactive behavior; Hypersomnias; Hypothalamic structure; Imaging Techniques; Impaired cognition; Impairment; Interpersonal Relations; Lateral; Learning; Linear Models; Magnetic Resonance Imaging; Master' s Degree; Measures; Medicine; Mentors; Metabolism; Modality; Napping; Narcolepsy; Neuraxis; Neuroanatomy; Neurology; Neuropeptides; Neurosciences; Neurosciences Research; Patients; Performance; Polysomnography; Positioning Attribute; Positron-Emission Tomography; Protocols documentation; Psychiatry; Radiology Specialty; Receptor Signaling; Recording of previous events; Relative (related person); Research; Research Personnel; Research Project Grants; Research Training; Rest; Risk; Role; Rye cereal; Schools; Scientist; Sleep; Symptoms; System; Techniques; Testing; Thalamic structure; Training; Translating; Universities; Wakefulness; Work; base; career; career development; clinical care; cognitive change; design; effective therapy; experience; gain of function; gamma-Aminobutyric Acid; hypocretin; image processing; improved; insight; meetings; neuroimaging; neuropsychiatry; patient oriented; relating to nervous system; research and development; skills; sleep drunkenness; socioeconomics; tool; white matter change

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.

描述（由申请人提供）：这份申请详细描述了职业发展计划和研究项目，旨在将Lynn Marie Trotti，医学博士，理学硕士，发展成为一名独立的临床研究员，专门从事嗜睡的评估和治疗，特别是在中枢神经系统嗜睡症方面的经验。这一建议建立在最近令人兴奋的发现之上，她帮助实现了嗜睡症患者脑脊液中GABA-A受体的内源性阳性变构调节剂。该提案利用她在临床研究领域的教育和早期在睡眠医学领域的科学努力，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David Rye医学博士（睡眠神经病学）、Carolyn Meltzer医学博士（放射学）、胡小平博士（生物医学工程）、Bruce Crosson博士（神经病学）和Helen Mayberg医学博士（神经病学/精神病学/放射学）组成。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。所有导师都有长期成功指导学员和初级教员的经验。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绩效提供了无与伦比的环境。Trotti博士的最终目标是将有关嗜睡病理生理学的发现转化为更有效的治疗这种致残症状的方法。为了实现这个长期目标，她在这个资助期有三个近期计划：1)精通设计、收藏和制作