Genetic Mechanisms of Epileptogenesis

癫痫发生的遗传机制

• 批准号: 8214513
• 负责人: RUSSELL JAMES FERLAND
• 金额: $ 33.61万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214513
• 关键词: Accounting; Affect; Age-Years; Animals; Behavior; Behavioral; Biochemical; Bioinformatics; Biological Markers; Brain; Brain Stem; Brain region; Brain-Derived Neurotrophic Factor; Cell Death; Cell Nucleus; Characteristics; Chromosomes, Human, Pair 7; Control Animal; Control Locus; Data; Data Set; Databases; Electroencephalography; Environment; Epilepsy; Epileptogenesis; Event; Family; Flurothyl; Gene Structure; Generalized seizures; Genes; Genetic; Genetic Heterogeneity; Genomics; Goals; Hippocampus (Brain); Human; Hypothalamic structure; Inbreeding; Individual; Inflammation; Lead; Location; Maps; Mediating; Medical Societies; Modeling; Molecular; Molecular Genetics; Molecular Structure; Mouse Strains; Mus; Mutation; Myoclonus; Neurons; Pathway interactions; Phase; Phenotype; Physiological; Population; Predisposition; Process; Prosencephalon; Quantitative Trait Loci; Recombinants; Recruitment Activity; Recurrence; Research; Resistance; Rest; Rodent Model; Role; Seizures; Severities; Staging; Symptoms; Syndrome; System; Testing; Time; Tissue-Specific Gene Expression; Variant; Work; candidate identification; congenic; design; gene discovery; insight; mRNA Expression; nervous system disorder; novel; prevent; public health relevance; therapy development; trait

DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological diseases in the world. This makes epilepsy a serious issue not only for those affected individuals and their families, but also for society and the medical profession. While many of the current treatments for epilepsy involve blocking the symptoms of the epilepsy, namely the seizures, there are few strategies that can ameliorate the ongoing reorganizational processes that are occurring in the epileptic brain. Therefore, elucidating the mechanisms responsible for this reorganization is vital for a better understanding of this process and for developing therapies that can ultimately prevent epilepsy. We have refined a rodent model of seizures using the chemoconvulsant, flurothyl. In this model, initial myoclonic jerk threshold, initial generalized seizure threshold, and two reorganizational/epileptogenic processes can be studied, 1) decreases in seizure threshold over 8 seizure trials and 2) alterations in seizure behavior, both of which occur over time. Our data suggest the hypothesis that there is significant genetic control of the processes underlying these reorganizational events observed in the repeated-flurothyl model as exemplified by differences observed between C57BL/6J and DBA/2J mice. Moreover, these traits segregate independently in C57BL/6J x DBA/2J (BXD) recombinant inbred (RI) lines. Thus, the goals of this proposal are to map quantitative trait loci (QTLs) in BXD animals that control each aspect of the flurothyl seizure characteristics observed, and determine the genetic and molecular pathways that mediate the reorganizational processes in the brain. We also will determine the neuroanatomical underpinnings of the reorganizational processes, which occur in the flurothyl model, through analysis of detailed neuroactivity maps in the brain, changes in brain circuitry following repeated seizures, and the role of BDNF in these processes. Lastly, we will utilize the extensive brain expression dataset in the genenetwork.org database to correlate differential gene expression in BXD brains with seizure phenotypes in an effort to identify potential biomarkers to predict the likelihood of seizure occurrence. The repeated-flurothyl model will allow for greater insight into the genetic control of the generalized seizure threshold and brain reorganization, and can also lead to the identification of QTLs (and the underlying genes) that are directly responsible for these processes, and move beyond studies that examine generalized seizure threshold solely. As a whole, these studies will provide greater insight into the process of brain reorganization from the genetic to the systems level. PUBLIC HEALTH RELEVANCE: Epilepsy is one of the most common neurological diseases, affecting approximately 1 - 4% of the total population by 80 years of age. While many of the current treatments for epilepsy involve blocking the symptoms of the epilepsy through seizures suppression, no current therapies target the ongoing epileptogenesis/reorganization that occurs in the epileptic brain. Our project is designed to better understand processes that are involved in the reorganization of the brain that accounts for the differences in seizure traits in different strains of mice. Our goal, using the repeated flurothyl model in mice, is to identify gene(s) and molecular processes that are altered following repeated seizures, accounting for the brain reorganization that can occur in the epileptic brain.

描述（由申请人提供）：癫痫是世界上最常见的神经系统疾病之一。这使癫痫病不仅对受影响的个人及其家人，而且对社会和医学界成为一个严重的问题。尽管目前的癫痫病治疗涉及阻止癫痫的症状，即癫痫发作，但很少有策略可以改善癫痫大脑中正在进行的重组过程。因此，阐明负责这种重组的机制对于更好地理解这一过程以及开发最终可以防止癫痫的疗法至关重要。 我们已经使用化学弹跳剂氟洛噻硫基完善了癫痫发作的啮齿动物模型。在此模型中，可以研究最初的肌阵挛性混蛋阈值，初始的广义癫痫发作阈值和两个重组/癫痫发作过程，1）在8个癫痫发作试验中癫痫发作阈值降低，而2）癫痫发作行为的改变，这两种都会随着时间的推移而发生。我们的数据表明，在重复的氟甲硫代模型中观察到的这些重组事件的基础过程中存在明显的遗传控制，这是由C57BL/6J和DBA/2J小鼠之间观察到的差异的例证。此外，这些特征在C57BL/6J X DBA/2J（BXD）重组（RI）线中独立隔离。因此，该提案的目标是绘制BXD动物中的定量性状基因座（QTL），以控制观察到的氟甲基癫痫发作特征的每个方面，并确定介导大脑中重组过程的遗传和分子途径。我们还将通过分析大脑中详细的神经活性图，重复癫痫发作后的脑电路变化以及BDNF在这些过程中的作用，通过分析大脑中详细的神经活性图，确定重组过程中发生的神经解剖学基础。最后，我们将利用genEnetwork.org数据库中广泛的大脑表达数据集将BXD大脑中的差异基因表达与癫痫发作表型相关联，以识别潜在的生物标志物以预测癫痫发作的可能性。 重复的氟甲硫代模型将使对广义性癫痫发作阈值和脑重组的遗传控制更深入，还可以导致直接造成这些过程的QTL（以及基础基因）的鉴定，并超越了研究广义癫痫发作阈值的研究。总体而言，这些研究将为从遗传到系统水平的大脑重组过程提供更深入的了解。 公共卫生相关性：癫痫是最常见的神经疾病之一，到80岁时影响总人口的1-4％。尽管当前的许多癫痫治疗方法涉及通过癫痫发作抑制阻止癫痫的症状，但目前没有疗法针对癫痫大脑中发生的持续癫痫发生/重组。我们的项目旨在更好地理解与大脑重组有关的过程，这些过程解释了不同小鼠菌株中癫痫发作性状的差异。我们的目标是使用小鼠中重复的雌激素模型，是鉴定重复癫痫发作后改变的基因和分子过程，这考虑了癫痫大脑中可能发生的大脑重组。