Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy
开发基于机制的策略来治疗化疗引起的周围神经病变
基本信息
- 批准号:10349764
- 负责人:
- 金额:$ 41.95万
- 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:2022-01-13 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAftercareAxonBehavioralBortezomibCancer ModelCancer PatientCancer SurvivorChemotherapy-Oncologic ProcedureChemotherapy-induced peripheral neuropathyCisplatinClinicClinicalCultured CellsDependovirusDevelopmentDiseaseDominant-Negative MutationDoseDose-LimitingDropsEnzymesHealthHematologyHyperalgesiaIn VitroInjectionsInterventionKnock-outLeadLifeMalignant NeoplasmsMediatingMetabolicMetabolismMethodsMultiple MyelomaMusNerveNerve DegenerationNerve FibersNeurologyNeuronsNeuropathyNiacinamideOncologyOther GeneticsPaclitaxelPainPathogenesisPathway interactionsPatientsPeripheral NervesPeripheral Nervous System DiseasesPharmaceutical PreparationsPhosphotransferasesPlasmaPreventionPrevention strategyProcessProteinsQuality of lifeSafetySavingsSpinal PunctureSterilitySymptomsTherapeuticTissuesToll-like receptorsToxic effectTranslatingTranslationsVincristineVirusWild Type MouseWorkanalogappropriate doseaxonal degenerationbasecancer therapychemotherapeutic agentchemotherapychemotherapy induced neuropathycofactorcostdisabilityeffective therapyeffectiveness testingevidence baseexperimental studyfunctional outcomesgene therapyheart metabolismimprovedin vivoleukemiametabolomicsmouse modelmultidisciplinaryneuroinflammationneurotransmissionnicotinamide-beta-ribosidenoveloral supplementationoverexpressionpreventprogramsselective expressionside effectsuccesstreatment durationtreatment strategytumor progression
项目摘要
Project Summary/Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently dose-limiting side-effect of
chemotherapeutic drugs. CIPN can be excruciatingly painful, profoundly debilitating, cause permanent disability,
and lead some patients to elect to end life-saving treatment. In contrast to other side effects, CIPN frequently
lasts well beyond the duration of treatment and can cause permanent disability. Consequently, therapies are
urgently needed as they would not only enhance the quality of life of cancer patients both during and after
treatment, but also improve cancer therapy by permitting effective chemotherapeutic dosing. To address this
need we have developed mechanism-based interventional strategies for CIPN.
Chemotherapy-induced neuropathies are characterized by axonal degeneration, which leads to the unpleasant
symptoms of neuropathies. We have shown that vincristine and bortezomib, two widely used chemotherapeutic
agents with different mechanisms of action act via the neuronal protein SARM1, the central executioner of a
genetically encoded axon degeneration program. Activated SARM1 cleaves the metabolic cofactor NAD+,
leading to local NAD+ depletion, followed by metabolic collapse and axon fragmentation. We here present several
new strategies to block this final common pathway to axon degeneration. We generated a SARM1
dominant/negative that potently inhibits SARM1 function and axon degeneration. We will utilize adeno-
associated virus (AAV) -mediated expression of a SARM1 dominant-negative to block SARM1 activity and will
assess the effect of SARM1-dominant/negative on axon degeneration, neuroinflammation and functional
outcomes. We have shown in vitro that boosting the synthesis of NAD+ strongly protects against vincristine and
bortezomib-induced axon degeneration. We will use virus-mediated expression of enzymes of the NAD+ salvage
pathway to boost NAD+ synthesis, which counters the axon destructive effects of SARM1. As a further step to
translation to the clinic, we will evaluate in mouse models of cancer whether our therapeutic strategies interact
with the cancer or chemotherapy and are effective in cancer-bearing mice. Success of our experiments will lead
directly to clinically viable means to prevent and treat CIPN.
项目总结/文摘
项目成果
期刊论文数量(0)
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Stefanie Geisler其他文献
Stefanie Geisler的其他文献
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{{ truncateString('Stefanie Geisler', 18)}}的其他基金
Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy
开发基于机制的策略来治疗化疗引起的周围神经病变
- 批准号:
10550224 - 财政年份:2022
- 资助金额:
$ 41.95万 - 项目类别:
Sarm1 Pathway: New Therapeutic Targets in Neuropathy
Sarm1 通路:神经病的新治疗靶点
- 批准号:
8868459 - 财政年份:2015
- 资助金额:
$ 41.95万 - 项目类别:
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