Development and testing of Carbon Quantum Dot architectures to arrest neurotoxicant-insult- related outcomes
开发和测试碳量子点架构以阻止神经毒物侮辱相关的结果
基本信息
- 批准号:10412365
- 负责人:
- 金额:$ 15.34万
- 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:2022-08-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcidsAddressAgricultureAlzheimer&aposs DiseaseAmyloidAmyloid FibrilsAmyloid ProteinsAmyloid beta-ProteinAnimal ModelAntioxidantsApoptosisArchitectureAttenuatedAutomobile DrivingBehavioralBiological AssayBiosensing TechniquesBlood - brain barrier anatomyCaenorhabditis elegansCarbonCell membraneCell modelCellsChemicalsChemistryComplexCoupledDataDevelopmentDiseaseDoseDrug Delivery SystemsEgg WhiteEpidemiologyEventExposure toExtravasationFluorescenceFruitGenerationsHeat-Shock Proteins 70HerbicidesHomeostasisHouseholdHumanHuntington DiseaseHuntington proteinImpairmentIn VitroIndustrial fungicideIndustrializationInjuryInsecticidesInsulinLigninLinkManebMeasuresMinorityMissionMitochondriaModelingMolecularMuramidaseNational Institute of Environmental Health SciencesNational Institute of General Medical SciencesNatural ProductsNematodaNerve DegenerationNeuroblastomaNeurodegenerative DisordersNeurologicNeuronal InjuryNeuronsNeurotoxinsNeurotransmittersOilsOrganismOutcomeOutputOxidative StressPaperParaquatParkinson DiseasePathologicPest ControlPesticidesPhytochemicalProphylactic treatmentProteomicsQuantum DotsReactive Nitrogen SpeciesReactive Oxygen SpeciesReportingResearchRisk FactorsRodent ModelRoleRotenoneSolubilityStressStudentsSurfaceTechniquesTestingTissue imagingToxic Environmental SubstancesToxic effectTranslatingUbiquitinUp-RegulationWomanWorkalpha synucleinamyloid formationamyloidogenesisbasebiomaterial compatibilitychemical synthesiscytotoxicitydesigndopaminergic neurongene therapyin vivoislet amyloid polypeptidelight scatteringlocomotor deficitmitochondrial dysfunctionmulticatalytic endopeptidase complexmutantnanomaterialsneuron lossneurotoxicnitrosative stressnovelorganic acidoverexpressionpesticide exposurepolyphenolpre-clinicalpreclinical trialpreventprotein aggregationresponsesmall moleculesuccesstheranosticstranslational potentialwasting
项目摘要
Exposure to pesticides, fungicides and herbicides is linked to neuronal injury, neuronal loss and the onset and progress of
neurodegeneration. Environmental and household use of pesticides such as rotenone, Maneb, paraquat, Cyprodinil, etc
initiates mitochondrial dysfunction. The resulting elevation in levels of reactive oxygen species (ROS) and reactive nitrogen
species (RNS) triggers ubiquitin-proteasome (UPS) dysregulation, alters cellular-proteomics’ status and the provokes the
aggregation of amyloid proteins in neurons. Aggregation-prone amyloids such as alpha-synuclein, amyloid β, and mutant
Huntingtin protein (mHTT) form toxic oligomers and protofibrils that create pores in cell membranes, disrupt Ca2+
homeostasis, facilitate neurotransmitter leakage and provoke neuronal death, on-setting neurodegenerative disorders such
as Parkinson’s (PD), Alzheimer’s (AD) and Huntington’s (HD) diseases. Efforts at limiting environmental toxicant-driven
neurodegenerative onset with small molecules have enjoyed limited success. Here, we explore whether a novel class of
carbon nano materials, viz. carbon quantum dots (CQDs), can restore cellular homeostasis and prevent behavioral deficits
in organisms under pesticide exposure. CQDs are easily synthesized from biowaste-containing carbon precursors such as
fruit peel, waste paper and organic acids via green-chemical techniques. They possess low cytotoxicity and are inherently
antioxidant. Importantly, they can be chemically functionalized and doped. When chemically tuned, they find applications
in biosensing, tissue imaging, drug-delivery and can cross the blood-brain barrier. Preliminary data from our lab has revealed
that organo-acid-derived CQDs can interfere in amyloid aggregation and mitigate ROS-stress in cells. They were uptaken
by nematodes and protected them from paraquat toxicity. We hypothesize that CQDs ameliorate environmental toxicant-
associated neuronal corruption. We test this hypothesis in Aim 1, by determining whether CQDs can intervene in amyloid
fibril-forming trajectories. We also attempt to extend our understanding of how functionalized CQDs interact with toxic
intermediates such as oligomers and protofibrils to passivate them. In Aim 2, using a number of proteomic and
neurometabolomic readouts, we establish whether functionalized CQDs can reset pesticide-driven cellular dyshomeostasis
in model neuroblastoma-derived cells. In Aim 3, we will test their ability to restore neuronal loss and behavioral deficits in
C. elegans using strains prone to amyloidogenesis and/or via pesticide-exposure. In the former scenario, worms strains
expressing mHTT, amyloid β or alpha-synuclein will be exposed to CQDs while the latter objective is completed by introducing
CQDs into pesticide-challenged worms. By quantitatively co-relating amyloid aggregation and locomotor compromise with
CQD-type and dose, we will test our hypothesis at the organismal level. Findings from the completion of the proposed work
will define the ability of green-chemistry-derived CQDs to attenuate pesticide-associated neuronal corruption. CQDs are
likely to translate to preclinical trials involving vertebrate (rodent) models of neurotoxic insult.
暴露于杀虫剂、杀菌剂和除草剂与神经元损伤、神经元丧失以及神经退化的发生和发展有关
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)
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Mahesh Narayan其他文献
Mahesh Narayan的其他文献
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{{ truncateString('Mahesh Narayan', 18)}}的其他基金
Development and testing of Carbon Quantum Dot architectures to arrest neurotoxicant-insult- related outcomes
开发和测试碳量子点架构以阻止神经毒物侮辱相关的结果
- 批准号:
10669598 - 财政年份:2022
- 资助金额:
$ 15.34万 - 项目类别:
Understanding PDI-related neurotoxicity and advancing preventative approaches
了解 PDI 相关的神经毒性并推进预防方法
- 批准号:
9476277 - 财政年份:2016
- 资助金额:
$ 15.34万 - 项目类别:
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