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: 9898286
• 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/9898286
• 关键词: Acute; Acute Brain Injuries; Amyloid beta-Protein; Anatomy; Animal Model; Animals; Appearance; Award; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Caring; Chronic; Clinic; Clinical; Development; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Electrophysiology (science); 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; comorbidity; controlled cortical impact; educational atmosphere; forest; improved; injured; innovation; instructor; medical schools; mossy fiber; neurophysiology; novel; prevent; protein expression; public health relevance; response; severe injury; 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：Robert Kotloski博士是癫痫卓越中心和William S.米德尔顿纪念退伍军人医院。他还是威斯康星州大学神经病学系的研究员和讲师。Kotloski博士在杜克大学医学院完成了医学博士/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病学的住院医师培训，并在威斯康星州大学获得了临床神经生理学奖学金，重点是癫痫。他正在申请VA CDA-2奖，以获得职业发展培训和科学研究的支持，成为一名独立的VA研究员。 环境：Kotloski博士将在VA和威斯康星州大学完成拟议的研究。这两个组织提供了一个非常合议的气氛和强大的机构支持，包括保护的时间，研究空间和设备。这种独特的近交系大鼠只能通过导师托马斯苏图拉博士的实验室获得，以前从未用于TBI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TBI，创伤后癫痫（PTE）及其合并症。通过他的导师，他将提高他对癫痫和TBI动物模型的知识，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（Vemuganti博士）。在这个提案的过程中，他将磨练他在手稿和赠款写作，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奖结束前独立竞争VA Merit Review资金。 研究项目：目前对创伤性脑损伤（如癫痫）的破坏性残留的了解受到缺乏有用动物模型的限制。然而，一个独特的，可塑性敏感的大鼠品系，选择增加点燃率，已表现出频繁的创伤后癫痫发作后，中度至重度TBI。这项提议的直接目标是检验一个假设，即在创伤性脑损伤后， 癫痫的发展之前是电生理活动和蛋白质表达的变化，其预测PTE的后期发生。目的1是表征自发电图变化和创伤后癫痫发作后，在独特的大鼠品系和远交大鼠。将研究两种互补品系的近交系大鼠，一种选择用于增加点燃率（可塑性敏感），另一种选择用于降低点燃率（可塑性抵抗），以及远系Sprague-Dawley大鼠。TBI将通过受控皮质撞击（CCI）诱导，并且将记录从损伤时间到PTE发展的电生理活动。这个目标的目的是确定TBI后和癫痫发作出现之前的电生理活动的变化，这将促进我们对这一关键但临床沉默期的理解，并可作为创伤后癫痫发生的生物标志物。目的二是探讨创伤后癫痫发生的分子机制。CCI后不同时间点来自三种遗传背景的大鼠脑的蛋白质表达模式将与PTE的存在或不存在相关。将研究已知参与TBI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GFAP。这一目标的目标是确定PTE发展的分子机制和大脑结构，这可以指导潜在治疗方法的开发。由于TBI和PTE影响了大量的退伍军人和平民，目前的诊断和治疗选择受到严重限制，因此对这种流行和具有挑战性的疾病的进一步了解将大大提高我们照顾这些人的能力。

项目成果

A machine learning approach to seizure detection in a rat model of post-traumatic epilepsy.

在创伤后癫痫的大鼠模型中，一种机器学习方法。

• DOI: 10.1038/s41598-023-40628-1
• 发表时间: 2023-09-22
• 期刊: Scientific reports
• 影响因子: 4.6