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
• 负责人: Mahesh Narayan
• 金额: $ 15.35万
• 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/10669598
• 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 gene; Impairment; In Vitro; 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; Organic Synthesis; 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; Role; Rotenone; Solubility; Stress; Surface; Techniques; Testing; Tissue imaging; Toxic Environmental Substances; Toxic effect; Translating; Ubiquitin; Underrepresented Students; Up-Regulation; Woman; Work; alpha synuclein; amyloid formation; amyloidogenesis; biomaterial compatibility; blood-brain barrier crossing; chemical synthesis; cytotoxicity; design; dopaminergic neuron; fungicide; 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; phosphoneuroprotein 14; 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.

接触杀虫剂、杀菌剂和除草剂与神经元损伤、神经元损失以及神经元损伤的发生和进展有关。 神经变性。鱼藤酮、代森锰、百草枯、嘧菌环胺等农药的环境和家庭使用 引发线粒体功能障碍。由此导致活性氧 (ROS) 和活性氮水平升高 物种（RNS）触发泛素蛋白酶体（UPS）失调，改变细胞蛋白质组学的状态并引发 淀粉样蛋白在神经元中的聚集。易于聚集的淀粉样蛋白，例如 α-突触核蛋白、β 淀粉样蛋白和突变体 亨廷顿蛋白 (mHTT) 形成有毒寡聚物和原纤维，在细胞膜上形成孔，破坏 Ca2+ 体内平衡，促进神经递质渗漏并引起神经元死亡，引发神经退行性疾病，例如 如帕金森病 (PD)、阿尔茨海默病 (AD) 和亨廷顿病 (HD)。限制环境毒物驱动的努力 小分子治疗神经退行性疾病的成功有限。在这里，我们探讨是否存在一类新颖的 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 在接触农药的生物体中。 CQD 很容易由含有生物废物的碳前体合成，例如 通过绿色化学技术生产果皮、废纸和有机酸。它们具有低细胞毒性并且本质上 抗氧化剂。重要的是，它们可以进行化学功能化和掺杂。经过化学调整后，它们找到了应用 用于生物传感、组织成像、药物输送，并且可以穿过血脑屏障。我们实验室的初步数据显示 有机酸衍生的 CQD 可以干扰淀粉样蛋白聚集并减轻细胞中的 ROS 应激。他们被采纳了 线虫，并保护它们免受百草枯毒性。我们假设 CQD 可以改善环境毒物- 相关的神经元腐败。我们在目标 1 中通过确定 CQD 是否可以干预淀粉样蛋白来检验这一假设 原纤维形成轨迹。我们还尝试扩展我们对功能化 CQD 如何与有毒物质相互作用的理解 中间体如低聚物和原纤维来钝化它们。在目标 2 中，使用了一些蛋白质组学和 神经代谢组读数，我们确定功能化 CQD 是否可以重置农药驱动的细胞稳态失调 在模型神经母细胞瘤衍生细胞中。在目标 3 中，我们将测试他们恢复神经元损失和行为缺陷的能力 使用易于淀粉样蛋白生成和/或通过农药暴露的菌株的线虫。在前一种情况下，蠕虫菌株 表达 mHTT、β 淀粉样蛋白或 α-突触核蛋白将暴露于 CQD，而后一个目标通过引入来完成 CQD 进入受农药挑战的蠕虫。通过定量地将淀粉样蛋白聚集和运动损害与 CQD 类型和剂量，我们将在有机体水平上检验我们的假设。完成拟议工作的结果 将定义绿色化学衍生的 CQD 减轻农药相关神经元腐败的能力。 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。