Development of in vivo probes to study the function of TRIP8b in cognition
开发体内探针来研究 TRIP8b 在认知中的功能
基本信息
- 批准号:10665810
- 负责人:
- 金额:$ 82.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelArrhythmiaBindingBiochemicalBiologicalBiological AssayBiologyBiophysicsBrainBrain regionCardiacCellsCellular AssayCharacteristicsChemicalsChronicChronic stressCognitionCognitiveCognitive deficitsCyclic NucleotidesDataDevelopmentDorsalDrug TargetingElectrophysiology (science)Flow CytometryGeneticHeartHigh PrevalenceHippocampusImpaired cognitionImpairmentIn VitroKnock-outKnowledgeLearningLong-Term PotentiationMajor Depressive DisorderMediatingMemoryMental HealthMental disordersMethodsMolecularMolecular TargetMusNeuronsNootropic AgentsPathway interactionsPerformancePharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePharmacotherapyPhenotypePlayProcessPropertyPublishingReportingRisk FactorsRoleSeriesSpecificitySurfaceSymptomsTestingToxic effectTranslational ResearchValidationWorkanalogcognitive changecognitive processcommon symptomcyclic-nucleotide gated ion channelsexperimental studyhigh throughput screeninghippocampal atrophyhippocampal pyramidal neuronimprovedin vivoinhibitorinsightinterestmouse modelneuronal excitabilityneuropsychiatric disordernovelpharmacologicreduce symptomsresponsescaffoldside effectsmall moleculesmall molecule inhibitorsocial defeattherapeutic targettherapy designtooltraffickingtranslational medicinevalidation studies
项目摘要
Abstract
Cognitive dysfunction is a common feature of neuropsychiatric diseases related to chronic stress. These
symptoms can be debilitating, and despite the high prevalence of illnesses like Major Depressive Disorder,
there are relatively few treatment options. To better address these symptoms, novel molecular targets are
needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in regulating
excitability in the hippocampus, a brain region critically involved in cognition. To avoid cardiac side effects
associated with antagonizing HCN channels (which are also expressed in the heart), our group has focused
on TRIP8b, a neuron-specific subunit of HCN channels. In our recently published report (Lyman et al, in
press at Science Translational Medicine), we established that chemogenetically disrupting the interaction
between TRIP8b and HCN in the dorsal hippocampus is sufficient to rescue impairments in cognition after
chronic stress. Combined, these results are consistent with the hypothesis that a small molecule that disrupts
the TRIP8b-HCN interaction could rescue the cognitive dysfunction seen after chronic stress. In order to
capitalize on this discovery, our group recently executed a high throughput screen to identify small molecule
inhibitors of the TRIP8b-HCN interaction. We identified one candidate scaffold which shows promising activity
as a TRIP8b inhibitor. This compound series serves as the basis for our current submission in which we
propose further medicinal chemistry optimization to develop TRIP8b inhibitors for use as chemical probes in
order to study TRIP8b in vivo. In our enclosed preliminary data, we show that our inhibitor potently disrupts
the interaction between TRIP8b and HCN in cells with negligible toxicity. This inhibition produces robust
effects on Ih, the current mediated by HCN channels both in vivo and in vitro. To expand upon this work, we
propose three aims. In Aim 1, we will perform iterative medicinal chemistry optimization to develop
compounds with improved potency and pharmaceutical characteristics. Compounds that perform well in our
biochemical and biophysical assays will be advanced to cellular assays in Aim 2 in order to determine if they
are capable of disrupting the TRIP8b-HCN interaction. In Aim 3 we will utilize our compounds in vivo to study
their effect on hippocampal function. Promising compounds will be investigated for their ability to rescue
cognitive deficits that result from chronic social defeat, an animal model of chronic stress. These experiments
will enable us to develop TRIP8b inhibitors that can be used as chemical probes to study the role of HCN
channels in regulating cognitive dysfunction after chronic stress.
摘要
认知功能障碍是与慢性应激相关的神经精神疾病的共同特征。这些
症状会使人衰弱,尽管像重度抑郁症这样的疾病很普遍,
治疗选择相对较少。为了更好地解决这些症状,
needed.超极化激活的环核苷酸门控(HCN)通道在调节细胞内的信号转导中起着关键作用。
海马体的兴奋性,一个与认知密切相关的大脑区域。为了避免心脏副作用
与拮抗HCN通道(也在心脏中表达)相关,我们的团队专注于
TRIP 8b是HCN通道的神经元特异性亚基。在我们最近发表的报告(莱曼等人,在
出版社在科学转化医学),我们建立了化学遗传学破坏的相互作用,
TRIP 8b和HCN在背侧海马中的相互作用足以挽救认知障碍,
慢性压力结合起来,这些结果与一种小分子干扰的假设是一致的。
TRIP 8b-HCN相互作用可以挽救慢性应激后观察到的认知功能障碍。为了
利用这一发现,我们小组最近进行了一项高通量筛选,
TRIP 8b-HCN相互作用的抑制剂。我们确定了一个候选支架,它显示出有希望的活性
TRIP 8b抑制剂这一化合物系列是我们目前提交的基础,
提出进一步的药物化学优化,以开发TRIP 8b抑制剂用作化学探针,
为了在体内研究TRIP 8b。在我们所附的初步数据中,我们表明我们的抑制剂有效地破坏了
TRIP 8b和HCN在细胞中的相互作用具有可忽略的毒性。这种抑制产生了强大的
对体内和体外HCN通道介导的电流Ih的影响。为了扩大这项工作,我们
提出三个目标。在目标1中,我们将进行迭代药物化学优化,以开发
具有改进的效力和药物特性的化合物。在我们的环境中表现良好的化合物
在目标2中,生物化学和生物物理测定将被推进到细胞测定,以确定它们是否
能够破坏TRIP 8b-HCN相互作用。在目标3中,我们将利用我们的化合物在体内研究
对海马功能的影响有希望的化合物将被调查的能力,拯救
认知缺陷是由长期的社会失败造成的,这是一种慢性压力的动物模型。这些实验
将使我们能够开发TRIP 8b抑制剂,可用作化学探针来研究HCN的作用
通道调节慢性应激后认知功能障碍。
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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Dane M Chetkovich其他文献
Dane M Chetkovich的其他文献
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{{ truncateString('Dane M Chetkovich', 18)}}的其他基金
Development of in vivo probes to study the function of TRIP8b in cognition
开发体内探针来研究 TRIP8b 在认知中的功能
- 批准号:
10644201 - 财政年份:2022
- 资助金额:
$ 82.5万 - 项目类别:
Investigating the Role of the Dorsal Hippocampus to Nucleus Accumbens Pathway in Regulating Social Interaction
研究背侧海马到伏核通路在调节社会互动中的作用
- 批准号:
10381577 - 财政年份:2021
- 资助金额:
$ 82.5万 - 项目类别:
Investigating the Role of the Dorsal Hippocampus to Nucleus Accumbens Pathway in Regulating Social Interaction
研究背侧海马到伏核通路在调节社会互动中的作用
- 批准号:
10195843 - 财政年份:2021
- 资助金额:
$ 82.5万 - 项目类别:
Characterizing antidepressant-like effects of a novel peptide HCN channel inhibitor
表征新型肽 HCN 通道抑制剂的抗抑郁样作用
- 批准号:
9617909 - 财政年份:2018
- 资助金额:
$ 82.5万 - 项目类别:
Characterizing antidepressant-like effects of a novel peptide HCN channel inhibitor
表征新型肽 HCN 通道抑制剂的抗抑郁样作用
- 批准号:
9322763 - 财政年份:2017
- 资助金额:
$ 82.5万 - 项目类别:
Discovery of novel small molecule antidepressants
新型小分子抗抑郁药的发现
- 批准号:
9263004 - 财政年份:2016
- 资助金额:
$ 82.5万 - 项目类别:
Discovery of novel small molecule antidepressants
新型小分子抗抑郁药的发现
- 批准号:
9038165 - 财政年份:2016
- 资助金额:
$ 82.5万 - 项目类别:
Evaluation of antidepressant-like effects of hippocampal HCN channel modulation
海马 HCN 通道调节的抗抑郁样作用评价
- 批准号:
8824404 - 财政年份:2014
- 资助金额:
$ 82.5万 - 项目类别:
Evaluation of antidepressant-like effects of hippocampal HCN channel modulation
海马 HCN 通道调节的抗抑郁样作用评价
- 批准号:
8923343 - 财政年份:2014
- 资助金额:
$ 82.5万 - 项目类别:
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