Preventing Tau uptake by novel inhibitors of tau binding to LRP1
通过与 LRP1 结合的新型 tau 抑制剂阻止 Tau 摄取
基本信息
- 批准号:10343473
- 负责人:
- 金额:$ 88.57万
- 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:2022-03-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmericanAnimal ModelAntibodiesAntisense OligonucleotidesAutomationBindingBiochemicalBiological AssayBiologyBiophysicsBrainBrain regionCellsCellular biologyChemicalsCritical PathwaysDNADementiaDiseaseDisease ProgressionDoseEventFluorescence Resonance Energy TransferFutureGoalsHealthcare SystemsHumanImpaired cognitionIn VitroInterventionLDL-Receptor Related Protein 1LeadLearningLibrariesLigand Binding DomainMeasuresMediatingMediator of activation proteinMedicalMorphologic artifactsMusNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenesisPathologicPathologyPathway interactionsPatientsPatternPenetrationPerformancePharmaceutical PreparationsPhenotypePowder dose formProbabilityProceduresProductionPropertyPublishingReagentRecombinant ProteinsSeriesSiteSocietiesSurfaceSystemTauopathiesTestingValidationWorkanalogbasecheminformaticseffective therapyhigh throughput screeningin vivo Modelin vivo evaluationinduced pluripotent stem cellinhibitorinsightknock-downmemberneurofibrillary tangle formationneurotoxicitynew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspreventprotein aggregationprototypereceptorresponsescaffoldscale upscreeningsmall moleculesmall molecule librariestau Proteinstau aggregationtau interactiontau mutationtreatment strategyuptake
项目摘要
PROJECT SUMMARY
Several neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by the spread and
aggregation of the protein tau. Tau aggregates or neurofibrillary tangles (NFTs) accumulate throughout the brain
of patients and lead to dementia. No effective treatments currently exist for tauopathies. Those approaches that
have been considered, such as tau antibodies and antisense oligonucleotides, directly target tau. The complexity
of tau cell biology, however, makes this approach challenging. A completely novel approach is to take advantage
of the tau spreading pathway. The spread of NFTs correlate with disease progression and is a likely mediator
for the observed neurotoxicity. Recently, we identified a cellular receptor, LRP1 (Low-density lipoprotein
Receptor-related Protein 1), that regulates the tau spread pathway. Knockdown of LRP1 prevents tau spread
in human iPS neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be an important
entry point for disease intervention. Therefore, the main objective of this project is to identify small-molecule
chemical probes that prevent the binding of tau to LRP1, with the hypothesis that these molecules would serve
as key starting points for novel therapeutics. In preliminary work, we have identified the primary interaction
surface for tau on LRP1 and have developed a TR-FRET high-throughput screening (HTS) assay to identify
compounds that can disrupt this interaction. We have optimized the assay to 1536-well format and conducted a
pilot screen of 5,000 compounds with excellent performance, Z'~0.7 and a hit rate of ~0.4%. Analysis of the 20
hits from this screen in primary, artifact, and orthogonal assays identified several compounds with modest
potency in dose response. To fully develop this work, we propose three aims. In Aim 1, we will use the TR-FRET
assay to screen a 420,000 chemical library and, in parallel, conduct an affinity screen of a 4.4-billion-
member DNA encoded library leveraging the DELopen platform (WuXi AppTec). In Aim 2, we will narrow our hit
selection using orthogonal and novel biochemical profiling assays to determine mechanism of action. Finally, in
Aim 3 we will validate hits with advanced biophysical and cell-based assays. We expect our multi-pronged
approach will identify multiple chemical series with different mechanisms of action. Subsequent hit expansion
efforts will produce chemical probes with properties suitable to test our hypothesis that small molecule LRP1-tau
inhibitors can prevent tau uptake and spread. In future studies we intend to develop these probes into drugs that
prevent tau spreading in tauopathies such as AD. As the critical path testing funnel is in place, we anticipate we
can rapidly obtain and evaluate selective in vitro hits, explore their activity, and ultimately their suitability as
starting points for hit-to-lead studies and for future in vivo evaluation in animal models and eventually patients.
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)
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 }}
Michael Jackson其他文献
Michael Jackson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('Michael Jackson', 18)}}的其他基金
Targeting the mutant promoter of Telomerase Reverse Transcriptase (TERT)
靶向端粒酶逆转录酶 (TERT) 的突变启动子
- 批准号:
10677899 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Brain-penetrant GPR88 agonists as novel therapeutics for opioid abuse
脑渗透性 GPR88 激动剂作为阿片类药物滥用的新型疗法
- 批准号:
10517225 - 财政年份:2022
- 资助金额:
$ 88.57万 - 项目类别:
Preventing Tau uptake by novel inhibitors of tau binding to LRP1
通过与 LRP1 结合的新型 tau 抑制剂阻止 Tau 摄取
- 批准号:
10581565 - 财政年份:2022
- 资助金额:
$ 88.57万 - 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
- 批准号:
10183333 - 财政年份:2020
- 资助金额:
$ 88.57万 - 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
- 批准号:
10400863 - 财政年份:2020
- 资助金额:
$ 88.57万 - 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
- 批准号:
10595660 - 财政年份:2020
- 资助金额:
$ 88.57万 - 项目类别:
Optimization and Characterization of "MYC Degraders" for Pediatric Medulloblastoma
小儿髓母细胞瘤“MYC 降解剂”的优化和表征
- 批准号:
10612251 - 财政年份:2020
- 资助金额:
$ 88.57万 - 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
- 批准号:
10037550 - 财政年份:2020
- 资助金额:
$ 88.57万 - 项目类别:
Developing Choroid Plexus-Based Tools and Drug Screens
开发基于脉络丛的工具和药物筛选
- 批准号:
9304373 - 财政年份:2016
- 资助金额:
$ 88.57万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 88.57万 - 项目类别:
Continuing Grant














{{item.name}}会员




