Genetic Determinants of Epilepsy in Murine Systems

小鼠系统中癫痫的遗传决定因素

• 批准号: 10653182
• 负责人: TRISTAN T SANDS
• 金额: $ 96.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653182
• 关键词: Acceleration; Address; Adult; Age; Attention; Behavior; Brain; Brain Diseases; Childhood; Childhood Neurological Disorder; Clinic; Clinical; Collaborations; Complement; Complex; Dedications; Development; Disease; Engineering; Enterobacteria phage P1 Cre recombinase; Epilepsy; Etiology; Family; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Heterogeneity; Genetic Models; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; In Situ; Individual; Intervention; Laboratories; Methods; Modeling; Molecular; Monitor; Mus; Mutation; Nature; Neurodevelopmental Disorder; Neurologic; Neurons; Paper; Pathogenicity; Pediatric Hospitals; Pharmacology; Pharmacotherapy; Phenotype; Precision therapeutics; Publishing; RNA; Role; Seizures; Series; Symptoms; System; Testing; Time; Variant; Vermont; Work; cell type; clinical application; collaborative approach; comorbidity; design; developmental genetics; effective therapy; epileptic encephalopathies; epileptiform; exome sequencing; expectation; gene discovery; gene therapy; genetic disorder diagnosis; in vivo; insight; mouse genetics; mouse model; nervous system disorder; novel therapeutic intervention; novel therapeutics; personalized approach; personalized medicine; precision medicine; programs; pup; side effect; success; tool; transcriptome; transcriptome sequencing

PROJECT SUMMARY Developmental and Epileptic Encephalopathies (DEE) are individually rare but collectively substantial neurodevelopmental disorders characterized by debilitating seizures and unremitting neurological comorbidities. Dedicated exome sequencing efforts have led to unprecedented success in DEE gene discovery, with one-third or more cases that are brought to the genetics clinic resulting in a clear genetic diagnosis. This new insight has, in turn, created high expectations for precision or personalized medicine to deliver new therapies to families who otherwise do not have many options for disease mitigation, since conventional drug therapy is ineffective for most symptoms in any given DEE. In principle, gene therapy offers potential for treating any symptom caused by a defective gene because it is based on replacing or eliminating it in situ. Among the barriers to clinical application include the mode and the timing of delivery, particularly for neurodevelopmental disease, and the concern about side effects from unintended impact on gene expression in cell types that do not require attention. The purpose and the design of this renewal proposal is to address these barriers directly using ready manipulable mouse models to examine key issues in the development and progression of DEE and the prospects for gene therapy. First, we will apply new methods explicitly designed to detect epileptiform activity and developmental milestones in mouse pups, representing an understudied but most appropriate age to model a childhood disease. We will then use mouse genetics tools to drive gene expression in different neuron types or developmental ages in these models, in order to determine the cellular etiology and critical window for disease development. Last, we will extend RNA-based gene therapy efforts to these models, testing for both effective mitigation of pathogenic features while monitoring accompanying changes in global gene expression. To accomplish these goals we have assembled a team of four laboratories each contributing complementary expertise. Through this synergistic, collaborative effort, we expect to make significant strides in understanding the basis of disease in three striking models of DEE with the potential to advance new treatments in the clinic.

项目总结 发育性和癫痫性脑病(DEE)是个别罕见的，但总体上是实质性的 神经发育障碍，以使人衰弱的癫痫发作和持续的神经共病为特征。 专心致志的外显子组测序工作在dee基因发现方面取得了前所未有的成功，有三分之一的人 或更多的病例被带到遗传学诊所，导致明确的基因诊断。这种新的洞察力已经， 反过来，人们对精准或个性化医学产生了很高的期望，以向那些 否则，没有太多缓解疾病的选择，因为传统的药物治疗对 在任何给定的Dee中，大多数症状。从原理上讲，基因疗法提供了治疗任何症状的可能性。 通过缺陷基因，因为它是基于在原位替换或消除它。临床面临的障碍之一 应用包括分娩的方式和时间，特别是对于神经发育疾病，以及 担心意外影响不需要注意的细胞类型中的基因表达的副作用。 本更新方案的目的和设计是使用可随时操纵的方式直接解决这些障碍 用小鼠模型研究DIE发生发展中的关键问题及基因研究前景 心理治疗。首先，我们将应用明确设计的新方法来检测癫痫样活动和发育 小鼠幼鼠的里程碑，代表了一个未被充分研究但最适合建立儿童疾病模型的年龄。 然后，我们将使用小鼠遗传学工具来驱动不同神经元类型或发育年龄的基因表达 在这些模型中，为了确定细胞病因学和疾病发展的关键窗口。最后的, 我们将把基于RNA的基因治疗努力扩展到这些模型，测试两种疾病的有效缓解 特征，同时监测伴随的全球基因表达的变化。为了实现这些目标，我们有 组建了一个由四个实验室组成的团队，每个实验室都提供互补的专业知识。通过这种协同作用， 共同努力，我们希望在理解疾病的基础上取得重大进展，在三个显著的方面 具有在临床上推进新治疗的潜力的DIE模型。

项目成果

Expression of the Neuronal tRNA n-Tr20 Regulates Synaptic Transmission and Seizure Susceptibility.

• DOI: 10.1016/j.neuron.2020.07.023
• 发表时间: 2020-10-14
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Kapur M;Ganguly A;Nagy G;Adamson SI;Chuang JH;Frankel WN;Ackerman SL
• 通讯作者: Ackerman SL

Genetic and phenotypic analysis of seizure susceptibility in PL/J mice.

PL/J 小鼠癫痫易感性的遗传和表型分析。

• DOI: 10.1007/s00335-004-3007-7
• 发表时间: 2004
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Kitami,Toshimori;Ernest,Sheila;Gallaugher,Laura;Friedman,Lee;Frankel,WayneN;Nadeau,JosephH
• 通讯作者: Nadeau,JosephH

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.

• DOI: 10.1016/j.celrep.2020.108303
• 发表时间: 2020-10-27
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Shore AN;Colombo S;Tobin WF;Petri S;Cullen ER;Dominguez S;Bostick CD;Beaumont MA;Williams D;Khodagholy D;Yang M;Lutz CM;Peng Y;Gelinas JN;Goldstein DB;Boland MJ;Frankel WN;Weston MC
• 通讯作者: Weston MC

Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel.

携带 szt1 突变的小鼠表现出癫痫易感性增加以及对作用于 m 通道的化合物的敏感性改变。

• DOI: 10.1111/j.0013-9580.2004.65703.x
• 发表时间: 2004
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Otto,JamesF;Yang,Yan;Frankel,WayneN;Wilcox,KarenS;White,HSteve
• 通讯作者: White,HSteve

A new spontaneous mouse mutation in the Kcne1 gene.

Kcne1 基因中一种新的小鼠自发突变。

• DOI: 10.1007/s003350010178
• 发表时间: 2000
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Letts,VA;Valenzuela,A;Dunbar,C;Zheng,QY;Johnson,KR;Frankel,WN
• 通讯作者: Frankel,WN