Integrated Platform for Discovery and Validation of Probes that Restore Protein Expression in Single-Gene Causes of Autism and Related Disorders
用于发现和验证可恢复自闭症及相关疾病单基因病因中蛋白质表达的探针的综合平台
基本信息
- 批准号:10153890
- 负责人:
- 金额:$ 65.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcademiaAllelesAnimal ModelAutomationBackBiologicalBiological AssayBiologyBrain DiseasesBudgetsChemicalsChildhoodDevelopmentDiseaseDisease modelDoseEnvironmentFundingGenesGeneticGenetic ModelsGoalsGrantHumanIndustrializationLearningLibrariesMagicMusNatureNeurodevelopmental DisorderNeuronsPatientsPharmaceutical PreparationsPhasePhenotypePlant RootsPositioning AttributePrecision therapeuticsProceduresProgress ReportsProteinsPublishingReadingReportingResearchRodentSeizuresSystemSystems DevelopmentTestingTherapeuticTranslatingTranslationsUnited States National Institutes of HealthValidationVariantWorkassay developmentautism spectrum disorderbasebrain cellcost effectivedesigndisease phenotypedrug candidatedrug discoveryflexibilityhigh throughput screeningimprovedin vivoinnovationminiaturizemouse modelnervous system disorderneuropsychiatric disordernovelpatient populationprotein expressionresponsescale upscreeningsmall molecule librariessubstance usetool
项目摘要
PROJECT SUMMARY
Drug discovery pipelines for neuropsychiatric disorders are dry. One approach to rejuvenating these
pipelines would be to create assays based on relevant disease phenotypes in primary neurons, something that
is currently lacking. However, a scalable assay development platform that is based on bona fide neurons,
remains cost effective, and that can support industrial level high-throughput screening (HTS) does not currently
exist. Over the past eight years (spread across different NIH-sponsored grants), our collaborative group has
created a flexible and scalable primary neuron-based assay development system that is compatible with
industrial-level HTS. Our long-standing goal for this project has been to optimize these procedures and
workflows to support neuron-based HTS phenotypic assays so that they can support very large
screening campaigns of up to 200K compounds.
We are happy to report that progress over the last budget period has pushed us closer toward this
stated goal. We have invented a state-of-the-art, disease-modeling assay created in primary neurons that is
designed to discover compounds that reverse the cellular consequences of genetic haploinsufficiency. Indeed,
a substantial proportion of childhood brain disorders are caused by single autosomal dominant variants
resulting in genetic haploinsufficiency. The rare genetic brain disorders that arise from these variants offer
great potential for translation because the disease mechanism is well-understood (i.e. low protein expression).
Therefore, a rationale precision therapy for treating genetic haploinsufficiency disorders would be to discover
“magic bullet” compounds that raise expression of functional proteins from the remaining undamaged allele
(e.g. “boosting compounds”). In this renewal project, we will employ technical innovations that have unlocked
the scalability of primary neurons for phenotypic HTS. As a proof-of-principle, we will scale-up and
implement an assay that reports reversal of low SynGAP expression in neurons caused by genetic
haploinsufficiency of the SYNGAP1/Syngap1 gene. We will miniaturize an HTS-compatible and disease-
modeling steady-state endogenous SynGAP expression assay so that it is compatible with industrial scale HTS
automation. Once implemented, we will then screen up to 200,000 unique substances using a completely
automated version of the neuron-based SynGAP expression assay. Finally, using a comprehensive multi-stage
biological validation funnel, we will identify and prioritize the most translatable chemical probes that raise
SynGAP protein expression. The overall impact of this project is that discovery of multiple, validated SynGAP
boosting compounds would provide proof-of-principle that our flexible platform is an effective tool for
phenotypic drug discovery for nervous system disorders.
项目总结
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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Courtney A Miller其他文献
Courtney A Miller的其他文献
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{{ truncateString('Courtney A Miller', 18)}}的其他基金
Development of the AI-driven model for anti-SUD drug development based on neuronal plasticity
基于神经元可塑性的人工智能驱动抗SUD药物开发模型的开发
- 批准号:
10467528 - 财政年份:2022
- 资助金额:
$ 65.22万 - 项目类别:
Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma
开发用于治疗胶质母细胞瘤的非肌肉肌球蛋白 II 抑制剂
- 批准号:
10557160 - 财政年份:2021
- 资助金额:
$ 65.22万 - 项目类别:
Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma
开发用于治疗胶质母细胞瘤的非肌肉肌球蛋白 II 抑制剂
- 批准号:
10524193 - 财政年份:2021
- 资助金额:
$ 65.22万 - 项目类别:
Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma
开发用于治疗胶质母细胞瘤的非肌肉肌球蛋白 II 抑制剂
- 批准号:
10595852 - 财政年份:2021
- 资助金额:
$ 65.22万 - 项目类别:
Impact of prenatal opioid exposure on long-range brain circuit connectivity and behavior
产前阿片类药物暴露对长程脑回路连接和行为的影响
- 批准号:
10163154 - 财政年份:2020
- 资助金额:
$ 65.22万 - 项目类别:
Impact of prenatal opioid exposure on long-range brain circuit connectivity and behavior
产前阿片类药物暴露对长程脑回路连接和行为的影响
- 批准号:
10060057 - 财政年份:2020
- 资助金额:
$ 65.22万 - 项目类别:
Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory
肌球蛋白 II 调节肌动蛋白动力学以及甲基苯丙胺和阿片类药物相关记忆的选择性脆弱性
- 批准号:
10533792 - 财政年份:2019
- 资助金额:
$ 65.22万 - 项目类别:
Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory
肌球蛋白 II 调节肌动蛋白动力学以及甲基苯丙胺和阿片类药物相关记忆的选择性脆弱性
- 批准号:
10596356 - 财政年份:2019
- 资助金额:
$ 65.22万 - 项目类别:
Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory
肌球蛋白 II 调节肌动蛋白动力学以及甲基苯丙胺和阿片类药物相关记忆的选择性脆弱性
- 批准号:
9916255 - 财政年份:2019
- 资助金额:
$ 65.22万 - 项目类别:
Integrated Platform for Discovery and Validation of Probes that Restore Protein Expression in Single-Gene Causes of Autism and Related Disorders
用于发现和验证可恢复自闭症及相关疾病单基因病因中蛋白质表达的探针的综合平台
- 批准号:
10371224 - 财政年份:2017
- 资助金额:
$ 65.22万 - 项目类别:
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