Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS
Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS
批准号:
9348132
负责人:
Brian C. Kraemer
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2021-03-31
关键词:
AffectAmyotrophic Lateral SclerosisBiological AssayBody WeightBrainCell modelCessation of lifeClinical TrialsCultured CellsDepositionDetergentsDevelopmentDiseaseDrug TargetingEvaluationExhibitsFamilial Amyotrophic Lateral SclerosisFamilyFutureGenesGeneticGoalsHumanKnock-outKnockout MiceLesionMediatingModelingMolecularMotorMotor CortexMotor Neuron DiseaseMotor NeuronsMusMutationNerve DegenerationNeuronsOnset of illnessPathogenicityPathologicPathologyPatientsPenetrancePenetrationPhosphorylationPhosphotransferasesProteinsResearchRoleSerineSpinal CordStructure-Activity RelationshipSymptomsSystemTestingTherapeuticTherapeutic InterventionToxic effectTransgenesTransgenic ModelValidationVeteransWorkdisabilitydisorder subtypedrug developmentdrug discoveryinhibitor/antagonistkinase inhibitormiddle agemortalitymotor neuron degenerationmouse modelneuron lossneuropathologyneurotoxicneurotoxicitypre-clinicalprematurepreventprotein TDP-43targeted treatmenttau-tubulin kinasetherapeutic candidatetherapeutic targettoolvirtual
中文摘要
TAR DNA结合蛋白43 kDa(TDP-43)是肌萎缩性侧索硬化症(AMO)患者的主要聚集性疾病蛋白。
侧索硬化症(ALS)。超过90%的ALS病例表现出含有洗涤剂的病理性病变
磷酸化、截短和泛素化TDP-43蛋白的不溶性沉积物。TDP-43
在S409/410磷酸化(pS409/410)是最一致的,稳健的,和特异性的神经病理学。
ALS的特征表明磷酸化TDP-43(pTDP)介导的神经毒性级联。
此外,pTDP已显示影响TDP-43在培养的细胞中的聚集和在细胞中的聚集。
人类ALS病例我们的前期工作证明了pS409/410 TDP-43介导运动神经元的运动
导致家族性ALS的TDP-43突变的毒性。存在调节TDP-43磷酸化的激酶
ALS治疗干预的一个有吸引力的目标。我们发现了一个保守的TDP-43-
具有翻译潜能的活性激酶,称为tau微管蛋白激酶1(TTBK 1)。脑识别
渗透TTBK 1抑制剂可能最终提供一个可行的药物开发策略。我们
假设TDP-43磷酸化增加驱动ALS中的运动神经元变性,
通过抑制TTBK 1来阻断pTDP积累将防止TDP-43介导的
ALS中的神经变性提出了三个综合的具体目标:1)确定TTBK 1
选择性激酶抑制剂。2)TTBK 1选择性抑制剂的优化和选择性抑制剂的验证
在pTDP积累的细胞模型中的化合物。3)验证TTBK 1在形成中的作用
使用TTBK 1敲除小鼠和现有的TDP-43蛋白质病转基因模型的pTDP。的
本文提出的研究将为TTBK 1选择性抑制剂的开发奠定基础
ALS的治疗方法
英文摘要
TAR DNA-binding protein 43 kDa (TDP-43) is the major aggregating disease protein in amyotrophic
lateral sclerosis (ALS). Over 90% of ALS cases exhibit pathological lesions containing detergent
insoluble deposits of phosphorylated, truncated, and ubiquitinated TDP-43 protein. TDP-43
phosphorylated at S409/410 (pS409/410) is the most consistent, robust, and specific neuropathological
feature of ALS suggesting a phosphorylated TDP-43 (pTDP) mediated cascade of neurotoxicity.
Furthermore pTDP has been shown to influence the aggregation of TDP-43 in cultured cells and in
human ALS cases. Our previous work demonstrated pS409/410 TDP-43 mediates motor neuron
toxicity of familial ALS-causing TDP-43 mutations. Kinases regulating TDP-43 phosphorylation present
an attractive target for therapeutic intervention in ALS. We have identified a well-conserved TDP-43-
active kinase with translational potential known as tau tubulin kinase 1 (TTBK1). Identification of brain
penetrant TTBK1 inhibitors may ultimately provide a viable drug development strategy. We
hypothesize that increased TDP-43 phosphorylation drives motor neuron degeneration in ALS and that
blocking pTDP accumulation by inhibiting TTBK1 will protect against TDP-43 mediated
neurodegeneration in ALS. Three integrated specific aims are proposed: 1) Identification of TTBK1
selective kinase inhibitors. 2) Optimization of TTBK1 selective inhibitors and validation of selective
compounds in a cellular model of pTDP accumulation. 3) Validation of the role of TTBK1 in the formation
of pTDP using TTBK1 knockout mice and an existing transgenic model of TDP-43 proteinopathy. The
studies proposed here will set the stage for development of TTBK1 selective inhibitors as a candidate
therapeutic approach for ALS.
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