High-throughput identification of molecular targets responsible for drug-induced peripheral neuropathies.
高通量鉴定导致药物引起的周围神经病变的分子靶标。
基本信息
- 批准号:10371819
- 负责人:
- 金额:$ 39.6万
- 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:2022-09-22 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAfferent NeuronsAftercareAnimalsAntineoplastic AgentsAxonBackCRISPR screenCRISPR/Cas technologyCell ProliferationCell SurvivalChronicClinicClinicalConfocal MicroscopyCutaneousCytotoxic ChemotherapyCytotoxic agentDataDermalDistalDoseDrug TargetingEmbryoFDA approvedFunctional disorderFutureImageIn VitroInterventionKnowledgeLarvaLeadLibrariesLigandsMaintenanceMalignant NeoplasmsMediatingMolecularMolecular TargetMorphologyMusNatural regenerationNervous system structureNeuronsNeuropathyPainPathway interactionsPatientsPeripheralPeripheral Nervous SystemPeripheral Nervous System DiseasesPharmaceutical PreparationsPharmacologyPharmacotherapyPhenotypePhosphotransferasesProcessProto-Oncogene Protein c-kitQuality of lifeRapid screeningReagentReceptor InhibitionReceptor Protein-Tyrosine KinasesRegimenReportingRoleSensorySeveritiesSignal PathwaySignal TransductionSkinSpinal GangliaSystemTestingTherapeuticTimeTissue SampleToxic effectTransgenic OrganismsTyrosine Kinase Receptor InhibitionWorkZebrafishaxon growthbasecancer cellcancer therapychemotherapydensitydosageeffective therapygenetic approachhuman tissueimaging platformin vivoinhibitorinhibitor therapyknock-downloss of functionmolecular drug targetmouse modelmutantneurotoxicneurotoxicitynew therapeutic targetnovel anticancer drugnovel therapeutic interventionpainful neuropathyprecision drugspreventreceptorresponsescreeningside effectsomatosensorytherapeutic targettime usetranslational study
项目摘要
Summary
Precision drug therapies have emerged as an effective and increasingly common form of cancer treatment.
These therapies frequently employ multi-kinase inhibitor drugs (MKIs) that each target multiple receptor
tyrosine kinases, sometime in combination with “conventional” cytotoxic chemotherapy drugs. One common
side effect of many cancer drug treatments is damage to the patient's peripheral nervous system, termed drug-
induced peripheral neuropathies (DIPNs). Most of these DIPNs are caused by the “dying back” of distal
sensory axons that innervate the skin, leading to sensory pain and dysfunction. Several commonly used MKIs
induce peripheral neuropathies, however, specific targets responsible for these painful DIPNs are unknown. To
address this knowledge gap, we established a high-content screening approach that allows rapid identification
of neurotoxic compounds in zebrafish. Using this approach, we showed that three MKIs known to produce
DIPNs in patients led to the reduced density of distal cutaneous somatosensory axons in zebrafish. Live
imaging demonstrated that axon retraction is the cellular basis for this reduced dermal axon density, consistent
with a “dying back” pathophysiology. Furthermore, these results were replicated in mouse dorsal root ganglia
neurons. Initial screening for MKI targets underlying this neurotoxic effect found that loss of the receptor
tyrosine kinase c-Kit, but not other shared kinase targets, led to reduced cutaneous axon density. c-Kit is
expressed in a subset of vertebrate sensory neurons in embryos and adults and its ligand SCF is expressed in
the skin, but the specific role of this ligand-receptor in axon maintenance or DIPNs has not been defined.
Importantly, application of one of these MKIs in c-kit mutants did not exacerbate axon density loss, indicating
that Kit is a major target for an MKI in the peripheral nervous system. Based on preliminary data we propose in
Aim 1 to: 1) implement a high-content screening approach in zebrafish to identify MKIs that induce distal
sensory axon toxicity in vivo and then identify their molecular targets; and 2) validate these results in
mammalian DRG culture. Aim 2 will characterize the downstream mechanisms underlying the neurotoxicity of
c-Kit receptor loss-of-function described in our preliminary data. Our work will identify and characterize the
molecular targets and cellular bases of painful MKI-induced peripheral neurotoxicity. This, in turn, will provide
new pathways and points of potential intervention to study in the context of a major, but unaddressed, clinical
problem in cancer drug therapies. In addition, we will also establish a workflow and reagents for future study of
candidate targets of DIPNs.
总结
精准药物疗法已成为一种有效且日益普遍的癌症治疗形式。
这些疗法经常使用多激酶抑制剂药物(MKI),每种药物靶向多个受体
酪氨酸激酶,有时与“常规”细胞毒性化疗药物联合使用。一个共同
许多癌症药物治疗的副作用是损害患者的外周神经系统,称为药物-
诱发性周围神经病变(DIPN)。这些DIPN中的大多数是由远端的“死回”引起的。
神经支配皮肤的感觉轴突,导致感觉疼痛和功能障碍。几种常用的MKI
然而,引起这些疼痛DIPN的具体靶点是未知的。到
为了解决这一知识差距,我们建立了一种高内容筛选方法,可以快速识别
神经毒性化合物。使用这种方法,我们发现三种已知产生
患者的DIPN导致斑马鱼远端皮肤体感轴突密度降低。生活
影像学显示,轴突收缩是这种真皮轴突密度降低的细胞基础,与
有着“濒死”的病理生理学此外,这些结果在小鼠背根神经节中被复制
神经元对这种神经毒性作用背后的MKI靶点的初步筛选发现,
酪氨酸激酶c-Kit,而不是其他共有的激酶靶点,导致皮肤轴突密度降低。c-Kit是
在胚胎和成年脊椎动物感觉神经元的亚群中表达,其配体SCF在
皮肤,但这种配体-受体在轴突维持或DIPN中的具体作用尚未确定。
重要的是,在c-kit突变体中应用这些MKI之一不会加剧轴突密度损失,表明
基特是MKI在周围神经系统中的主要目标根据我们提出的初步数据,
目的1:1)在斑马鱼中实施高内容筛选方法以鉴定诱导远端
体内感觉轴突毒性,然后鉴定它们的分子靶点;和2)验证这些结果,
哺乳动物DRG培养。目标2将描述神经毒性的下游机制
我们的初步数据中描述了c-Kit受体功能丧失。我们的工作将确定和表征
疼痛MKI诱导的外周神经毒性的分子靶点和细胞基础。这反过来又将提供
新的途径和潜在的干预点,以研究在一个主要的,但未解决的,临床
癌症药物治疗的问题。此外,我们还将建立一个工作流程和试剂,为今后的研究,
DIPN的候选目标。
项目成果
期刊论文数量(1)
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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Alex Nechiporuk其他文献
Alex Nechiporuk的其他文献
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{{ item.author }}
{{ truncateString('Alex Nechiporuk', 18)}}的其他基金
Protrusive behavior during collective cell migration
集体细胞迁移过程中的突出行为
- 批准号:
10595559 - 财政年份:2020
- 资助金额:
$ 39.6万 - 项目类别:
Protrusive behavior during collective cell migration
集体细胞迁移过程中的突出行为
- 批准号:
10376331 - 财政年份:2020
- 资助金额:
$ 39.6万 - 项目类别:
Protrusive behavior during collective cell migration
集体细胞迁移过程中的突出行为
- 批准号:
10386676 - 财政年份:2020
- 资助金额:
$ 39.6万 - 项目类别:
Isolation and interrogation of the transcriptional profile of pioneer neurons
先锋神经元转录谱的分离和询问
- 批准号:
9978397 - 财政年份:2020
- 资助金额:
$ 39.6万 - 项目类别:
Protrusive behavior during collective cell migration
集体细胞迁移过程中的突出行为
- 批准号:
10171597 - 财政年份:2020
- 资助金额:
$ 39.6万 - 项目类别:
Regulation of axon outgrowth by retrograde Ret signaling
通过逆行 Ret 信号调节轴突生长
- 批准号:
10633071 - 财政年份:2019
- 资助金额:
$ 39.6万 - 项目类别:
Regulation of axon outgrowth by retrograde Ret signaling
通过逆行 Ret 信号调节轴突生长
- 批准号:
10116506 - 财政年份:2019
- 资助金额:
$ 39.6万 - 项目类别:
Regulation of axon outgrowth by retrograde Ret signaling
通过逆行 Ret 信号调节轴突生长
- 批准号:
10364762 - 财政年份:2019
- 资助金额:
$ 39.6万 - 项目类别:
Genetic analyses of axon transport and microtubule dynamics in Zebrafish
斑马鱼轴突运输和微管动力学的遗传分析
- 批准号:
8688291 - 财政年份:2012
- 资助金额:
$ 39.6万 - 项目类别:
Genetic analyses of axon transport and microtubule dynamics in Zebrafish
斑马鱼轴突运输和微管动力学的遗传分析
- 批准号:
8873990 - 财政年份:2012
- 资助金额:
$ 39.6万 - 项目类别:
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