Identification and reversal of primary and secondary epileptogenic changes

原发性和继发性致癫痫变化的识别和逆转

• 批准号: 8823832
• 负责人: Steve C Danzer
• 金额: $ 34.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823832
• 关键词: Ablation; Abnormal Cell; Accounting; Animals; Axon; Brain; Brain Injuries; Cell physiology; Cells; Cellular Structures; Confounding Factors (Epidemiology); Data; Development; Disease; Effectiveness; Electroencephalography; Epilepsy; Epileptogenesis; Exhibits; Frequencies; Gene Mutation; Genetic; Genetic Recombination; Grant; Health; Hippocampus (Brain); Homologous Gene; Human; In Vitro; Knock-out; Lead; Life; Light; Mediating; Modeling; Monitor; Newborn Infant; Parents; Pathology; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Pilocarpine; Play; Population; Process; Proton Pump; Publishing; Research; Research Personnel; Role; Seizures; Series; Syndrome; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Time; brain malformation; design; diphtheria toxin receptor; granule cell; human FRAP1 protein; in vivo; mouse model; novel; optogenetics; phosphatase inhibitor; prevent; receptor expression; tensin

DESCRIPTION (provided by applicant): Elucidating the basic mechanisms by which a normal brain is transformed into an epileptic brain has been a holy grail of epilepsy research for decades. If the mechanisms of epileptogenesis can be understood, then new treatments and therapies can be designed to target these processes to prevent - and possibly cure - epilepsy. While years of research have revealed a multitude of changes that occur during epileptogenesis, one basic problem has been distinguishing changes that mediate epileptogenesis from changes that are associated with the disease, but play no causal role. This problem is evident for almost all existing models of epilepsy, which produce widespread brain damage and cellular changes, thereby making the proximal cause of the disease difficult to ascertain. For the present proposal, we make a pivotal advance by utilizing a novel mouse model of epilepsy generated in the first term of this grant, in which epilepsy develops following conditional, inducible deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from a subset (>5%) of hippocampal dentate granule cells (DGC). Excessive activation of the mTOR pathway is implicated in the development of temporal lobe epilepsy, and the effect of this deletion - to induce the abnormal integration of newborn DGC - is important because abnormal newborn DGC are a hallmark pathology of temporal lobe epilepsy, and are suspected of causing the disease. Our study provides direct evidence that abnormal DGC can cause epilepsy. Having demonstrating that abnormal DGC can be a proximal cause of epilepsy, we now seek to elucidate the mechanism(s) by which these cells promote seizures. Our guiding hypothesis is that abnormal DGCs promote epileptogenesis initially through cell-intrinsic increases in connectivity and activity, and secondarily by inducing changes among neighboring granule cells and their downstream targets. To test this hypothesis, we will determine the primary features of abnormal cells in SA1, the temporal associations between primary and secondary changes and epileptogenesis in SA2, and the functional significance of these changes in SA3 and 4.

描述（由申请人提供）：几十年来，阐明正常大脑转变为癫痫大脑的基本机制一直是癫痫研究的圣杯。如果可以理解癫痫发生的机制，那么就可以设计新的治疗方法和疗法来针对这些过程，以预防并可能治愈癫痫。虽然多年的研究揭示了癫痫发生过程中发生的多种变化，但一个基本问题是将介导癫痫发生的变化与与疾病相关但不起因果作用的变化区分开来。这个问题对于几乎所有现有的癫痫模型来说都很明显，这些模型会产生广泛的脑损伤和细胞变化，从而使疾病的直接原因难以确定。对于目前的提案，我们通过利用本次资助第一期产生的新型癫痫小鼠模型取得了关键进展，其中癫痫是在海马齿状颗粒细胞（DGC）子集（>5%）中条件性、诱导性删除mTOR通路抑制剂磷酸酶和张力蛋白同源物（PTEN）后发生的。 mTOR 通路的过度激活与颞叶癫痫的发展有关，这种缺失（诱导新生儿 DGC 异常整合）的作用非常重要，因为异常的新生儿 DGC 是颞叶癫痫的标志性病理，并被怀疑是导致该疾病的原因。我们的研究提供了异常 DGC 可能导致癫痫的直接证据。 在证明异常 DGC 可能是癫痫的近端原因后，我们现在试图阐明这些细胞促进癫痫发作的机制。我们的指导性假设是，异常的 DGC 最初通过细胞内在连接性和活性的增加来促进癫痫发生，其次通过诱导邻近颗粒细胞及其下游靶标之间的变化。为了检验这一假设，我们将确定 SA1 中异常细胞的主要特征、SA2 中原发性和继发性变化与癫痫发生之间的时间关联，以及 SA3 和 4 中这些变化的功能意义。