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: 10412365
• 负责人: Mahesh Narayan
• 金额: $ 15.34万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10412365
• 关键词: Acids; Address; Agriculture; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Antioxidants; Apoptosis; Architecture; Attenuated; Automobile Driving; Behavioral; Biological Assay; Biosensing Techniques; Blood - brain barrier anatomy; Caenorhabditis elegans; Carbon; Cell membrane; Cell model; Cells; Chemicals; Chemistry; Complex; Coupled; Data; Development; Disease; Dose; Drug Delivery Systems; Egg White; Epidemiology; Event; Exposure to; Extravasation; Fluorescence; Fruit; Generations; Heat-Shock Proteins 70; Herbicides; Homeostasis; Household; Human; Huntington Disease; Huntington protein; Impairment; In Vitro; Industrial fungicide; Industrialization; Injury; Insecticides; Insulin; Lignin; Link; Maneb; Measures; Minority; Mission; Mitochondria; Modeling; Molecular; Muramidase; National Institute of Environmental Health Sciences; National Institute of General Medical Sciences; Natural Products; Nematoda; Nerve Degeneration; Neuroblastoma; Neurodegenerative Disorders; Neurologic; Neuronal Injury; Neurons; Neurotoxins; Neurotransmitters; Oils; Organism; Outcome; Output; Oxidative Stress; Paper; Paraquat; Parkinson Disease; Pathologic; Pest Control; Pesticides; Phytochemical; Prophylactic treatment; Proteomics; Quantum Dots; Reactive Nitrogen Species; Reactive Oxygen Species; Reporting; Research; Risk Factors; Rodent Model; Role; Rotenone; Solubility; Stress; Students; Surface; Techniques; Testing; Tissue imaging; Toxic Environmental Substances; Toxic effect; Translating; Ubiquitin; Up-Regulation; Woman; Work; alpha synuclein; amyloid formation; amyloidogenesis; base; biomaterial compatibility; chemical synthesis; cytotoxicity; design; dopaminergic neuron; gene therapy; in vivo; islet amyloid polypeptide; light scattering; locomotor deficit; mitochondrial dysfunction; multicatalytic endopeptidase complex; mutant; nanomaterials; neuron loss; neurotoxic; nitrosative stress; novel; organic acid; overexpression; pesticide exposure; polyphenol; pre-clinical; preclinical trial; prevent; protein aggregation; response; small molecule; success; theranostics; translational potential; wasting

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.

暴露于农药，杀菌剂和除草剂与神经元损伤，神经元丧失以及开始和进展有关 神经变性。环境和家庭使用农药，例如烤面包酮，maneb，paraquat，cyprodinil等 启动线粒体功能障碍。由活性氧（ROS）和反应氮的水平升高 物种（RN）触发泛素 - 蛋白酶体（UPS）失调，改变细胞蛋白质组的状态和挑衅 神经元中淀粉样蛋白的聚集。聚集易受的淀粉样蛋白，例如α-核蛋白，淀粉样蛋白β和突变体 亨廷汀蛋白（MHTT）形成有毒的寡聚物和原纤维，在细胞膜中产生毛孔，破坏Ca2+ 稳态，促进神经递质泄漏并促进神经元死亡，设定神经退行性疾病此类 如帕金森氏症（PD），阿尔茨海默氏症（AD）和亨廷顿（HD）疾病。限制环境毒物驱动的努力 具有小分子的神经退行性发作取得了有限的成功。在这里，我们探索了一个新颖的课程 碳纳米材料，即。碳量子点（CQD）可以恢复细胞稳态并防止行为缺陷 在农药暴露下的生物中。 CQD很容易从含有生物管道的碳前体（例如 果皮，废纸和有机酸通过绿色化学技术。它们具有低细胞毒性，并且是继承的 抗氧化剂。重要的是，它们可以化学功能化和掺杂。化学调节后，他们发现应用 在生物传感，组织成像，药物传递并可以越过血脑屏障。我们实验室的初步数据揭示了 该有机酸衍生的CQD可以干扰淀粉样蛋白的聚集并减轻细胞中的Ros肌肉。他们被吸引了 通过线虫，保护它们免受帕拉奎特的毒性。我们假设CQD可以改善环境有毒物质 - 相关的神经元腐败。我们通过确定CQD是否可以干预淀粉样蛋白，在AIM 1中检验这一假设 原纤维形成轨迹。我们还试图扩展我们对功能化CQD与有毒的相互作用的理解 诸如低聚物和原纤维等中间体钝化它们。在AIM 2中，使用多种蛋白质组学和 神经代谢组读数，我们确定了功能化的CQD是否可以重置农药驱动的细胞dyshomeostasis 在AIM 3中，我们将测试他们恢复神经元丧失和行为缺陷的能力 秀丽隐杆线虫使用容易发生淀粉样蛋白发生和/或通过农药暴露的菌株。在前一种情况下，蠕虫菌株 表达MHTT，淀粉样β或α-突触核蛋白将暴露于CQD，而通过引入后一种物镜完成 CQD陷入农药挑战者的蠕虫中。通过定量共同关联的淀粉样蛋白聚集和运动妥协 CQD型和剂量，我们将在有机水平上检验我们的假设。拟议工作完成的结果 将定义绿色化学衍生的CQD减弱与农药相关的神经元腐败的能力。 CQD是 可能转化为涉及神经毒性损伤的脊椎动物（啮齿动物）模型的临床前试验。