Targeting MSUT2 with small molecules to ameliorate pathological tau
用小分子靶向 MSUT2 改善病理性 tau
基本信息
- 批准号:10735826
- 负责人:
- 金额:$ 218.13万
- 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:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAducanumabAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAmyloidAmyloid beta-ProteinAnimal ModelBindingBiologicalBiological AssayBrainBrain DiseasesCaenorhabditis elegansCellsClinical TrialsCognitiveDementiaDepositionDevelopmentDiagnosticDiseaseDoseDrug KineticsEvaluationExhibitsFrontotemporal Lobar DegenerationsFutureGoalsHumanImmunotherapeutic agentImmunotherapyImpaired cognitionInterventionInvestigationKnock-outLesionLibrariesMeasurementMeasuresMemoryMetabolismModificationMusNerve DegenerationNeurofibrillary TanglesNeuronsPathologicPathologyPenetrationPharmaceutical PreparationsPharmacodynamicsPhenotypePoly(A)+ RNAPredispositionPropertyProtein IsoformsRNA BindingRNA Recognition MotifRNA-Binding ProteinsRiskSafetySeveritiesStructure-Activity RelationshipTauopathiesTestingTherapeuticToxic effectTransgenic MiceValidationWorkanalogbrain tissuedesigngene conservationhigh throughput screeningin vivoinhibitormeetingsmouse modelneuroinflammationneuropathologyneuroprotectionneurotoxicitynew therapeutic targetnovelpharmacokinetics and pharmacodynamicspharmacologicpreservationpreventscreeningsmall moleculesmall molecule inhibitorsuccesssymptom treatmenttargeted treatmenttau Proteinstau aggregationtau-1therapeutic targettooltranslational study
项目摘要
Abstract
In frontotemporal lobar degeneration, Alzheimer’s disease (AD) and related tauopathies, tau neuropathology
correlates with severity of dementia. However, interventions for AD and AD related dementias (ADRDs) are
largely limited to treatment of symptoms that do not directly alter tau pathology or the resultant
neurodegeneration, with only one Aβ-directed immunotherapeutic (Aduhelm) recently receiving a controversial
accelerated approval for disease modification. Although investigation into additional Aβ targeted
immunotherapies continues, the obvious need remains for the development of tau-targeted disease-modifying
therapeutics. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the
mammalian brain. The mechanism of MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain
binding to poly(A) RNA, as deletion of the CCCH domain prevents neurodegeneration in animal models of
tauopathy. High throughput screening of over 100,000 high diversity compounds has identified many active dose-
responsive compounds that inhibit MSUT2 poly(A) RNA binding activity, including several classes of compounds
exhibiting promising structure-activity relationships. The identification of drug-like small molecules that inhibit
MSUT2 binding to poly(A) RNA will provide a pharmacological means of intervening against tauopathy. We
hypothesize that small-molecule inhibitors of MSUT2/poly(A) RNA binding will slow or reverse tau
pathology and the toxic consequences of pathological tau. The specific aims of this proposal are to optimize
potent and specific brain-penetrant MSUT2 inhibitors and use them to demonstrate proof-of-concept therapeutic
approaches to treating tauopathy. Successful completion of these aims will set the stage for future translational
studies by both generating MSUT2 specific tool compounds and further validating a novel therapeutic target for
pharmacological intervention in tauopathy disorders.
摘要
在额颞叶变性、阿尔茨海默病(AD)和相关的tau蛋白病、tau蛋白神经病理学中,
与痴呆的严重程度相关。然而,对AD和AD相关痴呆(ADRD)的干预措施,
很大程度上限于治疗不直接改变tau病理学或其结果的症状
神经变性,只有一个Aβ定向免疫(Aduhelm)最近接受了有争议的
加快疾病改良的审批。尽管针对其他Aβ的调查
尽管免疫疗法仍在继续,但仍然明显需要开发tau靶向的疾病修饰药物。
治疗学我们的工作已经证明,MSUT 2控制神经元对tau毒性的易感性。
哺乳动物的大脑MSUT 2调节tau蛋白病的机制涉及MSUT 2 CCCH结构域
与多聚(A)RNA结合,因为CCCH结构域的缺失防止了动物模型中的神经变性。
tau蛋白病高通量筛选超过100,000种高多样性化合物,已鉴定出许多活性剂量-
抑制MSUT 2 poly(A)RNA结合活性的响应性化合物,包括几类化合物
显示出有前景的结构-活性关系。药物样小分子抑制剂的鉴定
MSUT 2与poly(A)RNA的结合将提供干预tau蛋白病的药理学手段。我们
假设MSUT 2/poly(A)RNA结合的小分子抑制剂将减缓或逆转tau蛋白
病理学和病理性tau的毒性后果。该提案的具体目标是优化
有效和特异性的脑渗透MSUT 2抑制剂,并使用它们来证明概念验证治疗
治疗tau蛋白病的方法。这些目标的成功完成将为未来的翻译奠定基础。
通过生成MSUT 2特异性工具化合物并进一步验证用于治疗MSUT 2的新治疗靶点,
tau蛋白病病症的药理学干预。
项目成果
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Brian C. Kraemer其他文献
Erratum to: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
- DOI:
10.1186/s13024-015-0051-6 - 发表时间:
2015-10-23 - 期刊:
- 影响因子:17.500
- 作者:
Xi Chen;Hannah V. McCue;Shi Quan Wong;Sudhanva S. Kashyap;Brian C. Kraemer;Jeff W. Barclay;Robert D. Burgoyne;Alan Morgan - 通讯作者:
Alan Morgan
TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy
TMEM106B C 端片段聚集并驱动神经退行性蛋白病
- DOI:
10.1101/2024.06.11.598478 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Ruben Riordan;Aleen D. Saxton;P. McMillan;Rebecca L. Kow;Nicole F. Liachko;Brian C. Kraemer - 通讯作者:
Brian C. Kraemer
Yeast three-hybrid system to detect and analyze RNA-protein interactions.
用于检测和分析 RNA-蛋白质相互作用的酵母三杂交系统。
- DOI:
- 发表时间:
2000 - 期刊:
- 影响因子:0
- 作者:
Beilin Zhang;Brian C. Kraemer;D. Sengupta;S. Fields;Marvin Wickens - 通讯作者:
Marvin Wickens
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a <em>C. elegans</em> model of TDP-43 proteinopathy
- DOI:
10.1016/j.nbd.2018.06.013 - 发表时间:
2018-10-01 - 期刊:
- 影响因子:
- 作者:
Shi Quan Wong;Matthew G. Pontifex;Marie M. Phelan;Chandra Pidathala;Brian C. Kraemer;Jeff W. Barclay;Neil G. Berry;Paul M. O'Neill;Robert D. Burgoyne;Alan Morgan - 通讯作者:
Alan Morgan
Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD
- DOI:
10.1186/s13041-025-01174-1 - 发表时间:
2025-01-14 - 期刊:
- 影响因子:2.900
- 作者:
Randall J. Eck;Paul N. Valdmanis;Nicole F. Liachko;Brian C. Kraemer - 通讯作者:
Brian C. Kraemer
Brian C. Kraemer的其他文献
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{{ truncateString('Brian C. Kraemer', 18)}}的其他基金
Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology
Tau RNA 复合物的形成会破坏 tau 功能并驱动 tau 神经病理学
- 批准号:
10777174 - 财政年份:2023
- 资助金额:
$ 218.13万 - 项目类别:
Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease
开发 MSUT2 纳米抗体来靶向阿尔茨海默病中的病理性 Tau 蛋白
- 批准号:
10518408 - 财政年份:2022
- 资助金额:
$ 218.13万 - 项目类别:
Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease
开发 MSUT2 纳米抗体来靶向阿尔茨海默病中的病理性 Tau 蛋白
- 批准号:
10363866 - 财政年份:2022
- 资助金额:
$ 218.13万 - 项目类别:
Reversal of Tau Pathology with MSUT2 siRNA Conjugates
使用 MSUT2 siRNA 缀合物逆转 Tau 病理学
- 批准号:
10240452 - 财政年份:2020
- 资助金额:
$ 218.13万 - 项目类别:
Reversal of Tau Pathology with MSUT2 siRNA Conjugates
使用 MSUT2 siRNA 缀合物逆转 Tau 病理学
- 批准号:
9909831 - 财政年份:2020
- 资助金额:
$ 218.13万 - 项目类别:
Protection from pathological tau by activation of the ER unfolded protein response
通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白
- 批准号:
10347310 - 财政年份:2020
- 资助金额:
$ 218.13万 - 项目类别:
Protection from pathological tau by activation of the ER unfolded protein response
通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白
- 批准号:
10551219 - 财政年份:2020
- 资助金额:
$ 218.13万 - 项目类别:
Protection from pathological tau by activation of the ER unfolded protein response
通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白
- 批准号:
9901055 - 财政年份:2020
- 资助金额:
$ 218.13万 - 项目类别:
Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS
抑制病理性 TDP-43 磷酸化作为 ALS 的治疗策略
- 批准号:
9348132 - 财政年份:2017
- 资助金额:
$ 218.13万 - 项目类别:
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