PARP-1 activation in seizures and status epilepticus

简介(申请人提供)：项目摘要：黎一珍医生是一名具有董事会认证的儿科重症监护内科医生，长期对神经科学感兴趣。他在匹兹堡儿童医院完成了两年的T32研究员研究培训，目前是贝勒医学院的K12奖获得者，并参加了由K30赠款资助的临床科学家培训计划。他建议进一步发展事业，成为癫痫领域一名成功的、独立的调查员。他的主要研究兴趣是癫痫持续状态，这是一种儿童时期的流行疾病，与显著的死亡率和发病率有关。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。在许多脑病理中，PARP-1的激活与N-甲基-D-天冬氨酸介导的兴奋性毒性有关。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在癫痫持续状态时被激活。抑制PARP-1可以减少体内海马神经元的损伤，并在体外保护线粒体抵抗氧化应激的功能。他现在假设，PARP-1在癫痫持续状态下被激活，并与几种神经病理变化有关。他将研究：1.癫痫持续状态时海马PARP-1的激活，2.PARP-1激活对癫痫发作潜伏期、癫痫持续状态和海马区损伤的影响，以及3.PARP-1激活在癫痫持续状态后线粒体功能障碍中的作用。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·安德森(Anne E.Anderson)博士(癫痫)和威廉·J·克雷根(William J.Craigen)博士(线粒体生物学)都是各自领域的知名研究人员，在指导年轻教职员工方面都有出色的记录。赖博士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不同的研究兴趣，重点是癫痫，从而为进行翻译研究提供了丰富的智力环境。相关性：由于癫痫持续状态是一种普遍且具有潜在致命性的疾病，该提议的项目具有很大的临床意义。了解癫痫持续状态的病理过程将提供对其有害后果的洞察，并可能提出新的治疗干预措施。

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.