Project 3 - Development and investigation of murine models of channelopathy-associated epilepsy
项目 3 - 通道病相关癫痫小鼠模型的开发和研究
基本信息
- 批准号:10477456
- 负责人:
- 金额:$ 54.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAcuteAddressAdvanced DevelopmentAffectAmericanAnimalsAnticonvulsantsBrainBrain regionCell modelCellsClinicalCollaborationsCommunitiesDataDetectionDevelopmentDiseaseElectrophysiology (science)EpilepsyEquilibriumEtiologyEvaluationFunctional disorderGenesGeneticGoalsHippocampus (Brain)ImpairmentIn VitroInduced pluripotent stem cell derived neuronsInterneuronsInvestigationIon ChannelIon Channel GatingModelingMusMutationNeocortexNeonatalNeurologicNeuronal DysfunctionNeuronsPathogenesisPatientsPatternPharmaceutical PreparationsPharmacologyPhenotypePopulationPotassiumPrecision therapeuticsPropertyRegulatory ElementResearchSeizuresSeriesSliceSodiumStandardizationSyndromeSystemTestingTherapeuticTransgenic MiceTranslationsVariantbasebiophysical propertiescell typeclinically actionableearly onseteffectiveness evaluationepileptic encephalopathiesgenetic architecturein vivoin vivo Modelin vivo evaluationinfancyinsightmouse modelnervous system disorderprecision medicinepredictive modelingpreventresponsesynergismvoltage
项目摘要
PROJECT SUMMARY – PROJECT 3
Epilepsy is a common neurological disorder that affects over 3 million Americans and has a substantial genetic
contribution to its etiology. Mutation of voltage-gated ion channel genes (‘Channelopathies’), particularly
voltage-gated sodium (NaV) and potassium (KV) channel genes, have emerged as a major cause of early onset
epileptic encephalopathies. These severe epilepsy syndromes are often difficult to treat with existing therapies
and are associated with adverse neurodevelopmental sequelae, making them a high priority for better
treatment approaches like precision medicine. Functional characterization of a small number of epilepsy-
associated voltage-gated ion channel mutations in heterologous expression systems have demonstrated a
range of dysfunction, but it is presently difficult to extrapolate these results to in vivo effects. A major goal of
our Center is to determine how well in vitro cellular models predict neuronal dysfunction and pharmacological
responses in an intact brain. To accomplish this goal, Project 3 will focus on a series of representative mouse
models with NaV and KV channel variants that cause prototypical patterns of dysfunction. We hypothesize that
differences in the relative contribution of specific channels to excitability in various cell types within neuronal
networks determine the net effect on excitation-inhibition balance and influence pharmacological response.
Mouse models provide the opportunity to evaluate the effect of channel variants at the whole animal, cellular
and network levels, as well as to investigate pharmacological responses. In Aim 1, we will develop mouse
models to investigate NaV and KV channel variants associated with early onset epileptic encephalopathy.
Mouse lines will be evaluated for neurological phenotypes and pharmacological response in vivo. In Aim 2, we
will determine the impact of NaV and KV channel variants on channel properties and intrinsic cell excitability in
acutely dissociated neurons isolated from mouse models, and then determine the effectiveness of
pharmacological agents at normalizing channel activity and/or cell excitability in these neurons. These results
will be compared with similar recordings from heterologous expression systems (Project 1) and patient-specific
iPSC-derived neurons (Project 2) to establish important correlations between in vitro and in vivo models. In
Aim 3, we will determine the impact of NaV and KV channel variants on intrinsic properties of neurons and
consequent effects on network activity in brain slices, and then determine the effectiveness of pharmacological
agents at normalizing aberrant cellular and network excitability. Results from Project 3 will provide mechanistic
insight into the effects of channel dysfunction in intact brains, and determine therapeutic strategies that
normalize excitation-inhibition balance and prevent/reduce seizures. Synergy between this project and Projects
1 and 2 include cross-platform comparisons of the same channelopathy-associated epilepsy variants, which
will facilitate translation of results into valuable information for implementation of precision medicine in this
common neurological disorder.
项目总结-项目3
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jennifer A Kearney其他文献
Jennifer A Kearney的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jennifer A Kearney', 18)}}的其他基金
Genetic Mapping of Modifier Loci in a Mouse Model KCNB1 Encephalopathy
KCNB1 脑病小鼠模型修饰位点的遗传图谱
- 批准号:
10753301 - 财政年份:2023
- 资助金额:
$ 54.41万 - 项目类别:
Development of a novel anti-neuroinflammatory experimental therapeutic for epilepsy and Alzheimer's risk
开发一种针对癫痫和阿尔茨海默病风险的新型抗神经炎症实验疗法
- 批准号:
10255597 - 财政年份:2021
- 资助金额:
$ 54.41万 - 项目类别:
Project 3 - Development and investigation of murine models of channelopathy-associated epilepsy
项目 3 - 通道病相关癫痫小鼠模型的开发和研究
- 批准号:
10247560 - 财政年份:2018
- 资助金额:
$ 54.41万 - 项目类别:
Combined Approach to Genetic Modifiers of Inherited Epilepsy
遗传性癫痫基因修饰的综合方法
- 批准号:
9021876 - 财政年份:2014
- 资助金额:
$ 54.41万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 54.41万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 54.41万 - 项目类别:
Operating Grants