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
基本信息
- 批准号:10599259
- 负责人:
- 金额:$ 47.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAbnormal CellAnimal ModelAnimalsBenchmarkingBrainBrain InjuriesCell CountCellsCessation of lifeCollecting CellDevelopmentDiphtheria ToxinDiseaseDisinhibitionEpilepsyEpileptogenesisExhibitsFLP recombinaseFRAP1 geneFailureFrequenciesFunctional disorderGoalsGrantHippocampusHumanImpairmentIn VitroInterneuronsKnock-outKnockout MiceLeadMediatingMethodsModelingMonitorMusNational Institute of Neurological Disorders and StrokeNeuronsNewborn InfantPTEN geneParentsPathologyPathway interactionsPerforant PathwayPhysiologyPlayProcessRecurrenceResearchResearch PersonnelRoleSeizuresSeriesSeveritiesSliceTemporal LobeTemporal Lobe EpilepsyTestingTherapeuticViralWorkbrain malformationcombinatorialdensitydesigndesigner receptors exclusively activated by designer drugsdiphtheria toxin receptorexperimental studygranule cellin vivoinhibitory neuroninsightknockout animalmeetingsmouse modelneuron lossnovelphosphatase inhibitorpreventreceptor expression
项目摘要
Project Summary/Abstract
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 utilize a novel mouse model of epilepsy generated in
the first term of this grant, in which spontaneous cortical seizures develop following conditional, inducible
deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from >9% of hippocampal
dentate granule cells. The effect of this deletion – to induce the abnormal integration of newborn granule cells
– is important because abnormal newborn granule cells are a hallmark pathology of temporal lobe epilepsy,
and are suspected of causing the disease. Our model provides direct evidence that abnormal granule cells can
cause epilepsy, and creates an opportunity to understand how they cause the disease.
Work with this model has led us to hypothesize that spontaneous seizures in temporal lobe epilepsy
result from the combinatorial effects of intrinsically hyperexcitable granule cells and impaired inhibitory control
of these cells. To test this two-hit model of epileptogenesis, we will make full use of a unique feature of our
PTEN knockout model: the ability to manipulate the number or “load” of abnormal granule cells. We will
generate animals in which 5-8% of granule cells lack PTEN. These animals exhibit abnormal hippocampal
physiology, but not overt cortical seizures. This constitutes the first “hit”. We will then challenge these altered
circuits by silencing distinct classes of hippocampal inhibitory interneurons in vitro and in vivo – the second hit.
We predict that disinhibition will act synergistically with PTEN knockout granule cells to destabilize the
hippocampal circuit and promote seizures. The studies will provide a proof-of-concept test for how temporal
lobe epilepsy develops, and will provide insights into therapeutic strategies.
项目总结/摘要
阐明了正常大脑转变为癫痫大脑的基本机制,
几十年来一直是癫痫研究的圣杯。如果癫痫发生的机制能够被理解,
那么新的治疗和疗法就可以针对这些过程来预防--甚至治愈--
癫痫虽然多年的研究已经揭示了癫痫发生过程中发生的许多变化,
一个基本的问题是区分介导癫痫发生的变化和相关的变化,
与疾病有关,但不起因果作用。这个问题对于几乎所有现有的癫痫模型都是明显的,
这会造成广泛的脑损伤和细胞变化,从而使近端的原因,
疾病难以确定。对于目前的建议,我们利用了一种新的小鼠癫痫模型,
该补助金的第一个术语,其中自发性皮质癫痫发作在条件性,诱导性
mTOR通路抑制剂磷酸酶和张力蛋白同源物(PTEN)从海马的>9%的缺失
齿状颗粒细胞这种缺失的影响-诱导新生颗粒细胞的异常整合
- 是重要的,因为异常的新生颗粒细胞是颞叶癫痫的标志性病理学,
并被怀疑是致病原因我们的模型提供了直接证据,表明异常颗粒细胞可以
导致癫痫,并创造了一个机会来了解他们是如何导致疾病的。
对这个模型的研究使我们假设颞叶癫痫的自发性发作
结果从内在的过度兴奋颗粒细胞和受损的抑制控制的组合作用
这些细胞。为了测试这种癫痫发生的两次打击模型,我们将充分利用我们的一个独特的功能,
PTEN敲除模型:操纵异常颗粒细胞的数量或“负载”的能力。我们将
产生其中5-8%的颗粒细胞缺乏PTEN的动物。这些动物的海马
生理学上的,但不是明显的皮质癫痫这是第一个“打击”。然后我们将挑战这些改变了的
通过在体外和体内沉默不同类别的海马抑制性中间神经元的回路-第二次打击。
我们预测去抑制作用将与PTEN敲除颗粒细胞协同作用,使细胞不稳定。
海马回路和促进癫痫发作。这些研究将提供一个概念验证测试,
叶癫痫的发展,并将提供深入了解治疗策略。
项目成果
期刊论文数量(39)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hippocampal interneurons are direct targets for circulating glucocorticoids.
- DOI:10.1002/cne.25322
- 发表时间:2022-08
- 期刊:
- 影响因子:2.5
- 作者:Kraus, Kimberly L.;Chordia, Arihant P.;Drake, Austin W.;Herman, James P.;Danzer, Steve C.
- 通讯作者:Danzer, Steve C.
Impact of corticosterone treatment on spontaneous seizure frequency and epileptiform activity in mice with chronic epilepsy.
- DOI:10.1371/journal.pone.0046044
- 发表时间:2012
- 期刊:
- 影响因子:3.7
- 作者:Castro OW;Santos VR;Pun RY;McKlveen JM;Batie M;Holland KD;Gardner M;Garcia-Cairasco N;Herman JP;Danzer SC
- 通讯作者:Danzer SC
Contributions of Adult-Generated Granule Cells to Hippocampal Pathology in Temporal Lobe Epilepsy: A Neuronal Bestiary.
- DOI:10.3233/bpl-170056
- 发表时间:2018-08-10
- 期刊:
- 影响因子:0
- 作者:Danzer SC
- 通讯作者:Danzer SC
RU486 Mitigates Hippocampal Pathology Following Status Epilepticus.
- DOI:10.3389/fneur.2016.00214
- 发表时间:2016
- 期刊:
- 影响因子:3.4
- 作者:Wulsin AC;Herman JP;Danzer SC
- 通讯作者:Danzer SC
Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy.
- DOI:10.1371/journal.pone.0197955
- 发表时间:2018
- 期刊:
- 影响因子:3.7
- 作者:Wulsin AC;Franco-Villanueva A;Romancheck C;Morano RL;Smith BL;Packard BA;Danzer SC;Herman JP
- 通讯作者:Herman JP
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Steve C Danzer其他文献
Steve C Danzer的其他文献
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{{ truncateString('Steve C Danzer', 18)}}的其他基金
Anti-epileptogenic role of mTOR activation among hippocampal interneurons
海马中间神经元 mTOR 激活的抗癫痫作用
- 批准号:
10362959 - 财政年份:2021
- 资助金额:
$ 47.05万 - 项目类别:
Anti-epileptogenic role of mTOR activation among hippocampal interneurons
海马中间神经元 mTOR 激活的抗癫痫作用
- 批准号:
10534188 - 财政年份:2021
- 资助金额:
$ 47.05万 - 项目类别:
mTOR regulation of aberrant neuronal integration and epileptogenesis in epilepsy
mTOR 对癫痫中异常神经元整合和癫痫发生的调节
- 批准号:
9247850 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
Selective disruption of hippocampal dentate granule cells in autism: impact of PT
自闭症患者海马齿状颗粒细胞的选择性破坏:PT 的影响
- 批准号:
8056038 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
Selective disruption of hippocampal dentate granule cells in autism: impact of PT
自闭症患者海马齿状颗粒细胞的选择性破坏:PT 的影响
- 批准号:
8254431 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
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:
9258491 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
Short and long-term impact of neonatal seizures on hippocampal granule cell integ
新生儿癫痫发作对海马颗粒细胞整合的短期和长期影响
- 批准号:
7849034 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
mTOR regulation of aberrant neuronal integration and epileptogenesis in epilepsy
mTOR 对癫痫中异常神经元整合和癫痫发生的调节
- 批准号:
8887821 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
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:
9411798 - 财政年份:2009
- 资助金额:
$ 47.05万 - 项目类别:
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