PARP-1 activation in seizures and status epilepticus

项目简介：赖奕晨博士是一名儿科重症监护医师，长期对神经科学感兴趣。他在匹兹堡儿童医院作为T32研究员完成了两年的研究培训，目前是贝勒医学院的K12奖获得者，并参加了由K30资助的临床科学家培训计划。他提出进一步的职业发展，成为一个成功的，独立的研究者在癫痫领域。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疾病。在K12资助期间，Lai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的激活与n -甲基- d -天冬氨酸介导的许多脑病变的兴奋性毒性有关。然而，PARP-1在癫痫发作和癫痫持续状态中的作用尚未明确。他发现PARP-1在癫痫持续状态时被激活。PARP-1抑制降低了体内海马神经元损伤，保护了线粒体抗氧化应激功能。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改变。他将检查：1。癫痫持续状态下海马颞、细胞和亚细胞PARP-1的激活，2。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贡献。该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Anne E. Anderson博士（癫痫病）和William J. Craigen博士（线粒体生物学）都是各自领域的知名研究者，在指导年轻教员方面都有着出色的记录。Lai博士在该隐基金会实验室工作，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，因此为开展转化研究提供了丰富的智力环境。相关性：该项目具有重要的临床意义，因为癫痫持续状态是一种普遍且潜在致命的疾病。了解在癫痫持续状态中发生的病理过程将有助于了解其有害后果，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.