Development of Kv3.1 potentiators for correcting fast-spiking-interneuron hypofunction in schizophrenia and autism spectrum disorder
开发 Kv3.1 增效剂来纠正精神分裂症和自闭症谱系障碍的快速尖峰中间神经元功能减退
基本信息
- 批准号:10736465
- 负责人:
- 金额:$ 69.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAffectAmericanBehaviorBiological AssayBiologyBrainChemicalsClinical TreatmentCognitionCorpus striatum structureDNA Sequence AlterationDevelopmentDiseaseDrug KineticsElectrophysiology (science)EquilibriumFire - disastersFluorescenceFrequenciesGenesGeneticGoalsHigh Frequency OscillationHumanImpairmentIn VitroIndividualInterneuronsLibrariesManualsMolecular TargetMusMutationNucleus AccumbensOutputParvalbuminsPharmaceutical ChemistryPharmaceutical PreparationsPlayPotassium ChannelPrefrontal CortexProductivityPropertyQuality of lifeRoleSchizophreniaSensorySeriesShaw potassium channel protein familySliceSynaptic TransmissionTherapeuticVoltage-Gated Potassium Channelautism spectrum disordercostde novo mutationdesigndrug discoverydrug metabolismefficacy validationhigh rewardhigh riskhigh throughput screeningin vivoinformation processingmathematical modelmetermotor behaviormouse modelneural circuitneurodevelopmentneurotransmissionnovelpatch clamppharmacologicsmall moleculevoltage
项目摘要
SUMMARY
Genetic mutations or environmental insults that impair development of neural circuit connectivity can lead to
autism spectrum disorder (ASD) and schizophrenia, which together affect the quality of life, independence, and
productivity of millions of Americans and cost hundreds of billions of dollars annually. ASD and schizophrenia
are associated with an increased ratio of excitatory-to-inhibitory (E/I) synaptic transmission, raising the possibility
that drugs that are capable of restoring E/I balance could treat both disorders. GABAergic parvalbumin-
expressing fast-spiking interneurons (PV-INs) play critical roles in regulating inhibitory output in striatal networks
and coordinating high-frequency oscillations underlying cognition, sensory information processing, motor
behavior, and behavior, which are frequently disrupted in ASD and schizophrenia. The ability of PV-INs to fire
high-frequency action potentials (APs) is dependent on the expression of the voltage-gated potassium (K+)
channel Kv3.1, whose expression is largely restricted to PV-INs. De novo mutations in Kv3.1 are associated
with ASD in humans. A growing body of genetic, mathematical modeling, and pharmacological evidence
strongly suggests that small molecule potentiators/activators of Kv3.1 channel gating could promote PV-IN firing,
inhibitory output, and E/I balance. However, the dearth of potent and specific Kv3.1 channel potentiators with
suitable drug metabolism and pharmacokinetic (DMPK) properties has slowed efforts to critically evaluate the
therapeutic potential of Kv3.1 in treating ASD and schizophrenia. Here, we propose to employ a molecular target-
based drug discovery approach to develop 2-3 state-of-the-art Kv3.1 channel potentiators and then use them in
a mouse model of ASD to evaluate their ability to restore PV-IN excitability. In Aim 1, we will employ a fully
developed and validated fluorescence-based high-throughput screening (HTS) assay to interrogate
approximately 100,000 compounds from the Vanderbilt Institute of Chemical Biology library for novel Kv3.1
potentiators. Fluorescence and automated patch clamp electrophysiology assays will be used to identify potent,
selective, and chemically tractable compounds for further development. In Aim 2, an iterative cycle of medicinal
chemistry and functional assays will be used to optimize the potency, selectivity, and in vitro DMPK properties
of novel Kv3.1 potentiators. The studies outlined in Aim 3 will employ mouse brain slice electrophysiology to
evaluate the ability of optimized Kv3.1 potentiators restore PV-IN excitability in the nucleus accumbens and pre-
frontal cortex. We will specifically characterize the effects newly developed Kv3.1 potentiators on genetically
identified PV-IN current-voltage relationships, AP waveform, and firing frequency. This high-risk/high-reward
proposal will create unprecedented opportunities for pharmacologically modulating PV-IN excitability and
inhibitory output, critically evaluating the therapeutic value of Kv3.1 for modulating E/I balance, and potentially
impacting the clinical treatment of ASD and schizophrenia.
总结
基因突变或环境损伤会损害神经回路连接的发育,
自闭症谱系障碍(ASD)和精神分裂症,共同影响生活质量,独立性,
数百万美国人的生产力,每年花费数千亿美元。ASD和精神分裂症
与兴奋性与抑制性(E/I)突触传递的比率增加有关,这增加了
能够恢复E/I平衡的药物可以治疗这两种疾病。GABA能小清蛋白-
在纹状体网络中,表达快速发放的中间神经元(PV-IN)在调节抑制性输出中起着关键作用
以及协调认知、感觉信息处理、运动神经
行为和行为,这在ASD和精神分裂症中经常被破坏。PV-IN的击发能力
高频动作电位(AP)依赖于电压门控钾(K+)的表达,
通道Kv3.1,其表达主要限于PV-IN。
自闭症的人。越来越多的遗传学、数学模型和药理学证据
强烈表明Kv3.1通道门控的小分子增强剂/激活剂可以促进PV-IN放电,
抑制输出和E/I平衡。然而,缺乏有效的和特异性的Kv3.1通道增强剂,
合适的药物代谢和药代动力学(DMPK)性质已经减缓了对药物代谢和药代动力学(DMPK)的批判性评价的努力。
Kv3.1治疗ASD和精神分裂症的治疗潜力。在这里,我们建议使用分子靶点-
基于药物发现的方法来开发2-3种最先进的Kv3.1通道增强剂,然后将它们用于
ASD的小鼠模型,以评估它们恢复PV-IN兴奋性的能力。在目标1中,我们将充分利用
开发并验证了基于荧光的高通量筛选(HTS)试验,
来自范德比尔特化学生物学研究所库的约100,000种化合物用于新Kv3.1
增效剂。荧光和自动膜片钳电生理学测定将用于鉴定有效的,
选择性的和化学上易处理的化合物用于进一步开发。在目标2中,药物治疗的迭代周期
将使用化学和功能测定来优化效力、选择性和体外DMPK性质
新型Kv3.1增效剂。目标3中概述的研究将采用小鼠脑切片电生理学,
评价优化的Kv3.1增效剂恢复丘脑底核和前核中PV-IN兴奋性的能力,
额叶皮层我们将具体描述新开发的Kv3.1增效剂对基因表达的影响。
确定PV-IN电流-电压关系、AP波形和击发频率。高风险/高回报
该提案将为调节PV-IN兴奋性创造前所未有的机会,
抑制输出,批判性地评估Kv3.1调节E/I平衡的治疗价值,
影响ASD和精神分裂症的临床治疗。
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)
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Jerod S. Denton其他文献
A LRRC8 chimera with native functional properties is a heptamer with a large lipid-blocked pore
- DOI:
10.1016/j.bpj.2022.11.2466 - 发表时间:
2023-02-10 - 期刊:
- 影响因子:
- 作者:
Hirohide Takahashi;Toshiki Yamada;Jerod S. Denton;Kevin Strange;Erkan Karakas - 通讯作者:
Erkan Karakas
55: Rational Synthesis of a Selective Renal Outer Medullary Potassium Channel (ROMK) Antagonist
- DOI:
10.1053/j.ajkd.2010.02.062 - 发表时间:
2010-04-01 - 期刊:
- 影响因子:
- 作者:
Gautam Bhave;Brian A. Chauder;Rishin Kadakia;Eric S. Dawson;Craig W. Lindsley;C. David Weaver;Jerod S. Denton - 通讯作者:
Jerod S. Denton
Development of Small-Molecule Inhibitors of Proton-Activated Chloride Channels
- DOI:
10.1016/j.bpj.2019.11.3197 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Eric E. Figueroa;Jerod S. Denton - 通讯作者:
Jerod S. Denton
Oligomeric structure of LRRC8/VRAC channels: Arguments for a heptameric conformation
- DOI:
10.1016/j.bpj.2022.11.789 - 发表时间:
2023-02-10 - 期刊:
- 影响因子:
- 作者:
Jerod S. Denton;Toshiki Yamada;Hirohide Takahashi;Erkan Karakas;Kevin Strange - 通讯作者:
Kevin Strange
CysLT1 Receptor Antagonists Pranlukast and Zafirlukast Inhibit <em>LRRC8</em>-Mediated Volume Regulated Anion Channels Independently of the Receptor
- DOI:
10.1016/j.bpj.2019.11.3186 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Eric E. Figueroa;Jerod S. Denton - 通讯作者:
Jerod S. Denton
Jerod S. Denton的其他文献
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{{ truncateString('Jerod S. Denton', 18)}}的其他基金
Preclinical validation of Kir4.1/5.1 inhibitors for overcoming diuretic resistance
Kir4.1/5.1 抑制剂克服利尿剂抵抗的临床前验证
- 批准号:
10740429 - 财政年份:2023
- 资助金额:
$ 69.58万 - 项目类别:
Pharmacological Validation of Vascular KATP Channels for Modulating Ductus Arteriosus Tone
调节动脉导管张力的血管 KATP 通道的药理学验证
- 批准号:
10657531 - 财政年份:2020
- 资助金额:
$ 69.58万 - 项目类别:
Pharmacological Validation of Vascular KATP Channels for Modulating Ductus Arteriosus Tone
调节动脉导管张力的血管 KATP 通道的药理学验证
- 批准号:
10437919 - 财政年份:2020
- 资助金额:
$ 69.58万 - 项目类别:
Pharmacological Validation of Vascular KATP Channels for Modulating Ductus Arteriosus Tone
调节动脉导管张力的血管 KATP 通道的药理学验证
- 批准号:
10247076 - 财政年份:2020
- 资助金额:
$ 69.58万 - 项目类别:
Pharmacological Validation of Vascular KATP Channels for Modulating Ductus Arteriosus Tone
调节动脉导管张力的血管 KATP 通道的药理学验证
- 批准号:
10053976 - 财政年份:2020
- 资助金额:
$ 69.58万 - 项目类别:
Developing modulators of the sperm-specific potassium channel SLO3 for contraception
开发用于避孕的精子特异性钾通道 SLO3 调节剂
- 批准号:
10018521 - 财政年份:2019
- 资助金额:
$ 69.58万 - 项目类别:
Development of Distal Nephron Diuretics Targeting Kir4.1/5.1 Heteromeric Potassium Channels
针对 Kir4.1/5.1 异聚钾通道的远端肾单位利尿剂的开发
- 批准号:
10179370 - 财政年份:2019
- 资助金额:
$ 69.58万 - 项目类别:
Developing modulators of the sperm-specific potassium channel SLO3 for contraception
开发用于避孕的精子特异性钾通道 SLO3 调节剂
- 批准号:
10470966 - 财政年份:2019
- 资助金额:
$ 69.58万 - 项目类别:
Developing modulators of the sperm-specific potassium channel SLO3 for contraception
开发用于避孕的精子特异性钾通道 SLO3 调节剂
- 批准号:
10671550 - 财政年份:2019
- 资助金额:
$ 69.58万 - 项目类别:
Development of Distal Nephron Diuretics Targeting Kir4.1/5.1 Heteromeric Potassium Channels
针对 Kir4.1/5.1 异聚钾通道的远端肾单位利尿剂的开发
- 批准号:
10015266 - 财政年份:2019
- 资助金额:
$ 69.58万 - 项目类别:
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