PARP-1 activation in seizures and status epilepticus

癫痫发作和癫痫持续状态中的 PARP-1 激活

• 批准号: 7826592
• 负责人: Yi-Chen Lai
• 金额: $ 17.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826592
• 关键词: ADP ribosylation; Animals; Apoptotic; Biology; Brain Injuries; Brain Pathology; Cell Count; Cell Death; Cells; Childhood; Clinical; Clinical Oncology Supplement (K12); Cognitive deficits; Confocal Microscopy; Corpus striatum structure; D Aspartate; DNA; DNA Damage; Data; Development; Disease; Electrophoresis; Enrollment; Environment; Epilepsy; Experimental Models; Faculty; Failure; Foundations; Functional disorder; Funding; Genetic Transcription; Genome Stability; Grant; Health; Hippocampus (Brain); Impairment; Injury; Intensive Care; Label; Laboratories; Lead; Link; Measures; Mediating; Medicine; Membrane; Membrane Potentials; Mentors; Mitochondria; Morbidity - disease rate; N-Methylaspartate; Neuraxis; Neurological emergencies; Neuronal Injury; Neurons; Neurosciences; Nuclear; Outcome; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Oxygen Consumption; Parkinson Disease; Pathologic Processes; Pediatric Hospitals; Physicians; Play; Poly(ADP-ribose) Polymerases; Process; Proteins; Recurrence; Research; Research Personnel; Research Training; Rhodamine 123; Role; SECTM1 gene; Scientist; Seizures; Staining method; Stains; Status Epilepticus; Stroke; Time; Training Programs; Translational Research; Traumatic Brain Injury; Western Blotting; Work; apoptosis inducing factor; career development; cell type; clinically relevant; college; excitotoxicity; fluoro jade; in vivo; indexing; inhibitor/antagonist; inorganic phosphate; insight; interest; kainate; member; mitochondrial dysfunction; mitochondrial membrane; mortality; neurobehavioral; neuropathology; novel therapeutic intervention; programs; research study; skills; therapeutic target

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Dr. Yi-Chen Lai is a board-certified pediatric intensive care physician with a long-standing interest in neuroscience. He completed two years of research training as a T32 fellow at the Children's Hospital of Pittsburgh, and is currently a K12 award recipient at Baylor College of Medicine and is enrolled in the Clinical Scientist Training Program, funded by a K30 grant. He proposes further career development to become a successful, independent investigator in the field of epilepsy. His main research interest is status epilepticus, a prevalent disease of childhood associated with significant mortality and morbidity. During the K12 funding period, Dr. Lai has examined the role of poly(ADP-ribose) polymerase-1 (PARP-1) in status epilepticus. PARP-1 activation was associated with N-methyl-D-aspartate mediated excitotoxicity in many brain pathologies. However, the role of PARP-1 in seizures and status epilepticus remains undefined. He found that PARP-1 was activated during status epilepticus. PARP-1 inhibition decreased neuronal damage in the hippocampus in vivo, and preserved mitochondrial function against oxidative stress ex vivo. He now hypothesizes that PARP-1 is activated in status epilepticus and contributes to several neuropathological changes. He will examine: 1. the temporal, cellular and sub-cellular hippocampal PARP-1 activation in status epilepticus, 2. the effects of PARP-1 activation on the latency of seizures and status epilepticus and hippocampal damage, and 3. the contribution of PARP-1 activation to mitochondrial dysfunction following status epilepticus. This project will solidify Dr. Lai's research background in epilepsy and expand his skills to mitochondrial biology. His mentors, Dr. Anne E. Anderson (epilepsy) and Dr. William J. Craigen (mitochondrial biology) are well-established investigators in their respective fields, each with an excellent record in mentoring young faculty members. Dr. Lai is working in the Cain Foundation Laboratories, members of which have diverse research interests in clinical and basic neuroscience with a focus on epilepsy and thus provide a rich intellectual environment in which to conduct translational research. RELEVANCE: This proposed project has great clinical relevance as status epilepticus is a prevalent and potentially fatal disorder. Understanding the pathologic processes occurring in status epilepticus will provide insights into its detrimental consequences and possibly suggest novel therapeutic interventions.

描述（由申请人提供）：项目概述：赖毅晨博士是一名委员会认证的儿科重症监护医生，对神经科学有着长期的兴趣。他在匹兹堡儿童医院完成了为期两年的T32研究员研究培训，目前是贝勒医学院的K12获奖者，并参加了由K30资助的临床科学家培训计划。他建议进一步的职业发展，成为一个成功的，独立的研究人员在癫痫领域。他的主要研究兴趣是癫痫持续状态，这是一种与显著死亡率和发病率相关的儿童流行病。在K12资助期间，赖博士研究了聚（ADP-核糖）聚合酶-1（PARP-1）在癫痫持续状态中的作用。PARP-1激活与许多脑病理学中N-甲基-D-天冬氨酸介导的兴奋性毒性相关。然而，PARP-1在癫痫发作和癫痫持续状态中的作用仍不明确。他发现PARP-1在癫痫持续状态期间被激活。PARP-1抑制降低了体内海马中的神经元损伤，并保护了线粒体抗体外氧化应激的功能。他现在假设PARP-1在癫痫持续状态中被激活，并导致几种神经病理学变化。他将检查：1。癫痫持续状态时海马PARP-1的颞叶、细胞和亚细胞激活; 2. PARP-1激活对癫痫发作潜伏期、癫痫持续状态及海马损伤的影响。PARP-1激活对癫痫持续状态后线粒体功能障碍的作用。这个项目将巩固赖博士在癫痫方面的研究背景，并将他的技能扩展到线粒体生物学。他的导师，安妮·E博士。安德森（癫痫）和威廉·J·克雷根博士（线粒体生物学）是各自领域的知名研究人员，在指导年轻教师方面都有出色的记录。赖博士目前在凯恩基金会实验室工作，该实验室的成员在临床和基础神经科学方面有着不同的研究兴趣，重点是癫痫，从而为进行转化研究提供了丰富的知识环境。相关性：由于癫痫持续状态是一种普遍存在且可能致命的疾病，因此该拟定项目具有很大的临床相关性。了解癫痫持续状态发生的病理过程将提供其有害后果的见解，并可能提出新的治疗干预措施。