Osmotic therapy for seizures in pediatric traumatic brain injury

渗透疗法治疗小儿创伤性脑损伤癫痫发作

• 批准号: 9132374
• 负责人: Joseph C. Glykys
• 金额: $ 19.29万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132374
• 关键词: Acute; Acute Brain Injuries; Advisory Committees; Anticonvulsants; Area; Award; Barbiturates; Basic Science; Benzodiazepines; Binding; Brain; Brain Edema; Brain Injuries; Cessation of life; Characteristics; Child; Childhood; Chloride Ion; Chlorides; Clinical; Clinical Trials; Complement; Complication; Cytotoxic Cerebral Edema; Data; Dendritic Spines; Department chair; Development; Edema; Effectiveness; Electroencephalography; Electrophysiology (science); Environment; Epilepsy; Equipment; Faculty; Family; Foundations; Functional disorder; Funding; Funding Agency; General Hospitals; Goals; Hand; Health; Hippocampus (Brain); Hypoxia; Image; Imaging technology; In Vitro; Incidence; Injury; Intensive Care Units; Investigational Therapies; Knowledge; Lead; Learning; Mannitol; Massachusetts; Measurement; Measures; Mediating; Medical; Membrane Potentials; Mentors; Microscope; Microscopy; Modeling; Morbidity - disease rate; Motivation; Neocortex; Neonatal; Neuraxis; Neurologic; Neurology; Neuronal Injury; Neurons; Neurotransmitters; Paper; Patients; Pediatric Neurology; Pharmaceutical Preparations; Phenobarbital; Physiology; Population; Post-Traumatic Epilepsy; Property; Propofol; Proteins; Publications; Publishing; Records; Reducing Agents; Refractory; Research; Research Personnel; Rest; Rewards; Rodent; Scientist; Seizures; Slice; Targeted Research; Techniques; Technology; Temporal Lobe Epilepsy; Testing; Time; Training; Transgenic Mice; Translating; Traumatic Brain Injury; Water; Work; age group; base; career; experience; fluorescence imaging; fluorophore; gamma-Aminobutyric Acid; improved; in vitro Model; in vivo; in vivo imaging; injured; instructor; medical schools; mortality; neocortical; neonatal injury; novel therapeutics; pediatric traumatic brain injury; professional atmosphere; ratiometric; receptor; skills; two-photon

 DESCRIPTION (provided by applicant): The goal of this Mentored Clinical Scientist Research Career Developmental Award (K08) is to: A) Obtain skills in: in vivo multiphoton imaging, experience working with and culturing organotypic brain slices, and recording EEG in rodents. B) Have publications and preliminary data to submit a strong R01 application by the 4th year of the award. My final goal is to be an independent researcher in inhibition physiology and pediatric epilepsy, specifically in relation to traumatic brain injury (TBI). TBI is a leading caus of morbidity and mortality in the pediatric age group causing more than 50% of childhood deaths. Seizures are a common complication in pediatric TBI. How TBI leads to seizures is unclear. Several pathological conditions, including brain injury, induce an elevation of the neuronal chloride concentration [Cl-] i. The [Cl-] i am of great importance in neurons as Cl- flux through GABAA receptors mediate inhibition when [Cl-] i is lower than the neuron's resting membrane potential, but can lead to excitation if [Cl-] i is above the resting membrane potential. Our most recent publication has shown that mannitol, and osmotic agent used to treat brain edema in the Neurological Intensive Care Unit, not only decreases the neuronal volume, but also reduces [Cl-]i. Therefore, mannitol should have anti-convulsive properties. My proposal aims to answer the following hypothesis: mannitol (a prototypical hyperosmolar agent) reduces epileptiform activity in the neocortex due to a decrease in [Cl-] i. This decrease in [Cl-] i lead to an increase efficac of GABAAR mediated inhibition in a model of pediatric TBI. To answer this hypothesis, we will use in vitro / in vivo multiphoton imaging and electrophysiological techniques in a transgenic mouse that expresses a new Cl- sensitive radiometric fluorophore (SuperClomeleon). The K08 application, through courses and hands on experience, has been targeted to obtain the necessary skills in: A) multiphoton in vivo imaging; B) experience working with and culturing organotypic brain slices; C) recording and analyzing EEG in rodents. These techniques will allow me to complete my proposed project and give me the required technical knowledge to complement my current in vitro electrophysiology skills. I have a strong background in basic research and clinical pediatric neurology allowing me to understand and see the despair that families go through due to the limitations of post-traumatic epilepsy treatment. Furthermore, my 11 original published articles and my track record of competitive funding with at least one paper delivered per funding agency are evidence to my high motivation, ability to complete projects and my desire to continue a career in research targeted to neuronal inhibitory physiology and epilepsy. I am a full time faculty at Massachusetts General Hospital (MGH) in the Pediatric Neurology division of the Department of Neurology and an Instructor in Neurology at Harvard Medical School. I have the support of the Chair of the Department of Neurology and of the Chief of Pediatric Neurology to become a productive and independent researcher at MGH. With cutting edge technologies and facilities at MGH (2-photon microscopes, electrophysiological equipment), mentors with excellent track records (Dr. Staley, Dr. Bacskai), an advisory committee to discuss my research progress and translational possibilities (Dr. Rosand, Dr. Duhaime, Dr. Cash), the collaborative atmosphere at MGH and being part of Harvard Medical School, I am in a an excellent environment to develop a strong, productive and rewarding career as an independent researcher. The K08 training will be fundamental to help me succeed as an independent investigator.

 描述（由应用程序提供）：这一指导的临床科学家研究职业发展奖（K08）的目的是：a）获得：在体内多光子成像，使用和文化器官型脑切片的经验以及在啮齿动物中记录EEG。 b）有出版物和初步数据，可以在奖励的第四年提交强大的R01申请。我的最终目标是成为抑制生理和小儿癫痫的独立研究人员，特别是与脑损伤（TBI）有关。 TBI是小儿年龄组发病率和死亡率的主要原因，造成50％以上的儿童死亡。癫痫发作是小儿TBI的常见并发症。 TBI如何导致癫痫发作尚不清楚。包括脑损伤在内的几种病理条件会诱导神经元氯化物浓度的升高[Cl-]。当[Cl-] I低于神经元的静息膜电位时，[Cl-]在神经元中作为CL升级的神经元中非常重要，但是如果[Cl-] I在静息膜上高于静止的膜电位时，可能会导致兴奋。我们最近的出版物表明，甘露醇和渗透剂用于治疗神经系统重症监护病房中的脑水肿，不仅减少了神经元的体积，而且减少了[Cl-] i。因此，甘露醇应具有抗惊厥特性。我的提议旨在回答以下假设：甘露醇（一种典型的高质量剂）由于[Cl-] i的降低而降低了新皮层的癫痫表现。 [Cl-] i的下降导致加巴介导的抑制作用的有效性提高，而小儿TBI模型。为了回答这一假设，我们将在一种表达新的Cl敏感辐射荧光团（SuperClomeleon）的转基因小鼠中使用体外 /体内多光子成像和电生理技术。 K08应用程序通过课程和实力经验的目标是获得必要的技能： b）与文化有机脑切片合作的经验； c）记录和分析啮齿动物中的脑电图。这些技术将使我能够完成建议的项目，并为我提供所需的技术知识，以完成我当前的体外电生理学技能。我在基础研究和临床小儿神经病学方面具有强大的背景，使我能够理解并看到家庭经历了创伤后癫痫治疗的局限性的绝望。此外，我的11篇原始发表的文章和我的竞争资金往绩记录至少是每张资助机构提供的一篇论文，这是我的高动力，完成项目的能力以及我希望继续从事针对神经元抑制生理学和癫痫病的研究职业的证据。我是马萨诸塞州综合医院（MGH）的全职教职员工，神经病学小儿神经病学系，哈佛医学院的神经病学讲师。我得到了神经病学系主任和儿科神经病学系主的支持，成为MGH的一名富有成效的独立研究员。 With cutting edge technologies and facilities at MGH (2-photon microscopes, electrophysiological equipment), mentors with excellent track records (Dr. Staley, Dr. Bacskai), an advisory committee to discuss my research progress and translational possibilities (Dr. Rosand, Dr. Duhaime, Dr. Cash), the collaborative atmosphere at MGH and being part of Harvard Medical School, I am in a an excellent environment to develop a strong, Productive and rewarding career as an independent研究人员。 K08培训将是基本的，以帮助我成功成为独立研究员。