TBI and posttraumatic epilepsy in plasticity susceptible and resistant rats

 描述(由申请人提供)： 候选人：Robert Kotloski博士是癫痫卓越中心和威廉·S·米德尔顿纪念退伍军人医院创伤性脑损伤/多发伤(TBI)诊所的神经科工作人员。他也是威斯康星大学神经病学系的研究员和讲师。科特洛斯基博士在杜克大学医学院获得了医学博士学位，在此期间，他研究了癫痫发生的分子机制。他在维克森林大学完成了神经学住院医师学位，并在威斯康星大学获得了临床神经生理学奖学金，专注于癫痫。他正在申请退伍军人事务部CDA-2奖项，以获得职业发展培训和科学研究支持，成为一名独立的退伍军人事务部研究员。环境：Kotloski博士将在退伍军人管理局和威斯康星大学完成拟议中的研究。这两个组织都提供了异常融洽的氛围和强有力的机构支持，包括受保护的时间、研究空间和设备。这种独特的近交系大鼠只能通过导师Thomas Sutula博士的实验室获得，以前从未用于脑损伤研究。职业规划：Kotloski博士的长期职业目标包括建立一个独立的、富有成效的研究实验室，专注于了解脑外伤、创伤后癫痫(PTE)及其共病。通过他的导师，他将增强他对癫痫和脑外伤动物模型的知识，包括癫痫的细胞机制(Rutecki博士)和网络机制(Sutula博士)，以及脑损伤的分子机制(Vemuganti博士)。在这项建议的过程中，他将磨练他的手稿和资助写作、指导、演示和实验室管理方面的技能。Kotloski博士预计，拟议的研究和培训将使他能够在CDA-2奖项结束之前独立竞争退伍军人事务部功绩审查资金。研究项目：由于缺乏有用的动物模型，目前对脑损伤的破坏性残留物，如癫痫，的认识受到限制。然而，一种独特的、可塑性敏感的大鼠品系，由于点燃速度快而被选中，在中到重度脑创伤后表现出频繁的创伤后癫痫发作。这项提议的直接目标是检验这一假设，即在创伤性脑损伤后， 癫痫的发展是由电生理活动和蛋白表达的变化先于癫痫的，这些变化预示着PTE的发生。目的1研究不同品系大鼠和纯种大鼠脑外伤后自发脑电改变和创伤后癫痫发作的特点。将研究两个互补的近交系大鼠，一个选择点燃速度增加(可塑性敏感)，另一个选择点燃速度降低(可塑性抵抗)，以及远交配的SpragueDawley大鼠。通过控制皮质撞击(CCI)诱导脑损伤，并记录从损伤时到PTE的电生理活动。其目的是确定脑外伤后和癫痫发作出现之前电生理活动的变化，这将促进我们对这一关键但临床上沉默的时期的理解，并可作为创伤后癫痫发生的生物标志物。目的2是研究创伤后癫痫发生的分子机制。在CCI后的不同时间点，来自三种遗传背景的大鼠大脑的蛋白质表达模式将与PTE的存在或不存在相关。已知的参与脑损伤反应和癫痫发生的分子，包括脑源性神经营养因子、TrkB、Tau、Aβ和胶质纤维酸性蛋白，将被研究。这一目标的目的是确定PTE发生的分子机制和脑结构，从而指导潜在的治疗方法的发展。由于创伤性脑损伤和PTE影响了大量退伍军人和平民，而目前的诊断和治疗选择严重有限，因此对这种普遍和具有挑战性的疾病的了解将极大地提高我们照顾这些人的能力。

 DESCRIPTION (provided by applicant): Candidate: Dr. Robert Kotloski is a staff neurologist in the Epilepsy Center of Excellence and in the Traumatic Brain Injury/Polytrauma (TBI) clinics at the William S. Middleton Memorial Veterans Hospital. He is also a research fellow and instructor in the Department of Neurology at the University of Wisconsin. Dr. Kotloski has completed a combined MD/PhD degree at Duke University School of Medicine, during which time he studied molecular mechanisms of epileptogenesis. He has completed a residency in Neurology at Wake Forest University and a Clinical Neurophysiology fellowship with an epilepsy focus at the University of Wisconsin. He is applying for a VA CDA-2 award in order to obtain the career development training and support for scientific study to become an independent VA researcher. Environment: Dr. Kotloski will complete the proposed research at the VA and the University of Wisconsin. Both organizations provide an exceptionally collegial atmosphere and strong institutional support including protected time, research space, and equipment. The unique strains of in-bred rats are only available through the laboratory of a mentor, Dr. Thomas Sutula, and have not been used for TBI research previously. Career Plan: Dr. Kotloski's long-term career goals include the establishment of an independent, productive research laboratory focused on understanding TBI, post-traumatic epilepsy (PTE), and its comorbidities. Through his mentors, he will enhance his knowledge of animal models of epilepsy and TBI including cellular (Dr. Rutecki) and network (Dr. Sutula) mechanisms of epilepsy, and molecular mechanisms of TBI (Dr. Vemuganti). During the course of this proposal, he will hone his skills in manuscript and grant writing, mentoring, presentation, and laboratory management. Dr. Kotloski expects the proposed research and training will allow him to independently compete for VA Merit Review funding prior to the end of the CDA-2 award. Research Project: Current understanding of devastating residuals of TBI such as epilepsy is limited by a paucity of useful animal models. However a unique, plasticity-susceptible strain of rat, selected for increased rate of kindling, has demonstrated frequent post-traumatic seizures following moderate-to-severe TBI. The immediate goal of this proposal is to test the hypothesis that, following a traumatic brain injury, the development of epilepsy is preceded by changes in electrophysiologic activity and protein expression which are predictive of the later occurrence of PTE. Aim 1 is to characterize spontaneous electrographic changes and post-traumatic seizures after TBI in unique rat strains and out-bred rats. Two complementary strains of in-bred rats, one selected for increased rate of kindling (plasticity-susceptible) and another selected for decreased rate of kindling (plasticity-resistant), as well as out-bred Sprague-Dawley rats, will be studied. TBI will be induced by controlled cortical impact (CCI) and electrophysiologic activity will be recorded from the time of injury through the development of PTE. The goal of this aim is to identify changes in electrophysiologic activity following TBI and prior to the appearance of seizures, which would advance our understanding of this critical but clinically silent period, and which could serve as biomarkers for post-traumatic epileptogenesis. Aim 2 is to examine the molecular mechanisms underlying post-traumatic epileptogenesis. Protein expression patterns from the brains of rats from the three genetic backgrounds at various time points following the CCI will be correlated to the presence or absence of PTE. Molecules known to be involved in the response to TBI and in epileptogenesis, including BDNF, TrkB, Tau, Aβ, and GFAP, will be studied. The goal of this aim is to identify molecular mechanisms and brain structures underlying the development of PTE, which could guide the development of potential therapeutics. As TBI and PTE impact a significant number of Veterans and civilians, and current diagnostic and therapeutic options are severely limited, improved understanding of this prevalent and challenging disorder will greatly advance our ability to care for these individuals.