TBI and posttraumatic epilepsy in plasticity susceptible and resistant rats

可塑性敏感和抵抗大鼠的 TBI 和创伤后癫痫

• 批准号: 9031206
• 负责人: Robert Joseph Kotloski
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031206
• 关键词: Acute Brain Injuries; Amyloid beta-Protein; Animal Model; Animals; Appearance; Award; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Breeding; Caring; Clinic; Clinical; Comorbidity; Development; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Entropy; Environment; Epilepsy; Epileptogenesis; Equipment; Evaluation; Fellowship; Frequencies; Funding; Genetic; Glial Fibrillary Acidic Protein; Goals; Grant; Health; Health Expenditures; High Frequency Oscillation; Hour; Human; Immunoblotting; Immunohistochemistry; Impairment; Individual; Injury; Joints; Knowledge; Laboratories; Laboratory Research; Manuscripts; Mentors; Molecular; Neurologist; Neurology; Pattern; Population; Post-Traumatic Epilepsy; Preventive treatment; Process; Quality of life; Rat Strains; Rattus; Research; Research Personnel; Research Project Grants; Research Training; Residencies; Residual state; Resistance; Seizures; Sprague-Dawley Rats; Stimulus; Structure; Surveys; Testing; Therapeutic; Time; Training Support; Traumatic Brain Injury; Universities; Variant; Veterans; Veterans Hospitals; Wisconsin; Work; Writing; biomarker development; career; career development; combat; controlled cortical impact; educational atmosphere; forest; improved; injured; innovation; instructor; medical schools; mossy fiber; neurophysiology; novel; prevent; protein expression; public health relevance; response; skills; tau Proteins; therapeutic development; therapeutic target

 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.

 描述（由申请人提供）： 候选人：罗伯特·科特洛斯基（Robert Kotloski）博士是癫痫卓越中心的员工神经科医生，以及威廉·S·米德尔顿纪念退伍军人医院的脑损伤/脑损伤/多特拉马（TBI）诊所的诊所。他还是威斯康星大学神经病学系的研究研究员和讲师。 Kotloski博士在杜克大学医学院完成了MD/PHD学位，在此期间，他研究了癫痫发生的分子机制。他已经在威克森林大学（Wake Forest University）完成了神经病学的居住地，并在威斯康星大学（University of Wisconsin）癫痫病临床神经生理学研究金。他正在申请VA CDA-2奖，以获得职业发展培训和对科学研究的支持，以成为独立的VA研究员。环境：Kotloski博士将完成弗吉尼亚州和威斯康星大学的拟议研究。这两个组织都提供了一个异常的合作氛围和强大的机构支持，包括受保护的时间，研究空间和设备。植入大鼠的独特菌株只能通过心态的实验室Thomas Sutula博士获得，并且以前尚未用于TBI研究。职业计划：Kotloski博士的长期职业目标包括建立一个专注于了解TBI，创伤后癫痫（PTE）及其合并症的独立，生产研究实验室。通过他的导师，他将增强对癫痫和TBI动物模型的了解，包括癫痫的细胞（Rutecki博士）和网络（Sutula博士）机制，以及TBI的分子机制（Vemuguganti博士）。在本提案的过程中，他将是他在手稿和赠款写作，心理，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颁奖典礼结束之前独立竞争VA优异审查资金。研究项目：当前对TBI毁灭性残留物（例如癫痫）的理解受到有用动物模型的限制。然而，一种独特的，可塑性性的大鼠菌株被选择用于提高点燃速率，在中度至重度TBI后经常表现出创伤后癫痫发作。该提案的直接目标是检验以下假设：脑部受伤后， 癫痫的发育是在电生理活性和蛋白质表达的变化之前，这些变化可预测PTE的后期发生。目的1是表征独特的大鼠菌株和外饲料大鼠TBI后的赞助电气变化和创伤后癫痫发作。两只完整的孕荷大鼠菌株，一只用于提高点燃速率（可塑性），另一种是为了提高点燃速率（可塑性耐药性），以及外来繁殖的sprague-dawley大鼠，将研究。 TBI将由受控的皮质影响（CCI）诱导，并且将从PTE发展从损伤时期记录电生理活性。该目标的目的是确定TBI后和癫痫发作之前的电生理活性的变化，这将促进我们对这个关键但临床上沉默的时期的理解，并可以作为创伤后癫痫发生的生物标志物。目的2是检查创伤后癫痫发生后的分子机制。在CCI之后，来自三个遗传背景的大鼠大脑的蛋白质表达模式将与PTE的存在或不存在有关。已知参与对TBI和癫痫发生的分子，包括BDNF，TRKB，TAU，Aβ和GFAP，将研究。该目标的目的是确定PTE发展的基础的分子机制和大脑结构，这可以指导潜在治疗的发展。由于TBI和PTE影响了大量的退伍军人和平民，并且当前的诊断和治疗选择受到严重限制，因此对这种普遍和挑战障碍的理解得到了改善，将大大提高我们照顾这些人的能力。