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

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

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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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