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.

暴露于杀虫剂、杀真菌剂和除草剂与神经元损伤、神经元损失以及脑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，并引发细胞内蛋白质的降解。 神经元中淀粉样蛋白的聚集。易于聚集的淀粉样蛋白，如α-突触核蛋白、淀粉样蛋白β和突变体 亨廷顿蛋白（mHTT）形成有毒的寡聚体和原纤维，在细胞膜上产生孔，破坏Ca 2 + 内环境稳定，促进神经递质渗漏并引起神经元死亡，发生神经退行性疾病， 帕金森氏病（PD）、阿尔茨海默氏病（AD）和亨廷顿氏病（HD）。努力限制环境毒物驱动 用小分子治疗神经变性发作的成功有限。在这里，我们探讨是否有一类新的 碳纳米材料，即碳量子点（CQDs），可以恢复细胞内稳态并防止行为缺陷 在接触杀虫剂的生物体中。CQD容易由含生物废物的碳前体合成， 利用绿色化学技术，它们具有低细胞毒性， 抗氧化剂重要的是，它们可以被化学官能化和掺杂。经过化学调整后， 在生物传感、组织成像、药物输送中，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 并保护它们免受百草枯的毒害。我们假设CQDs改善了环境毒物- 相关的神经元腐败。我们在目标1中通过确定CQDs是否可以干预淀粉样蛋白来验证这一假设。 纤维形成轨迹我们还试图扩展我们对功能化CQDs如何与有毒物质相互作用的理解。 中间体如寡聚物和原纤维以使它们钝化。在目标2中，使用许多蛋白质组学和 神经代谢组学读数，我们确定功能化的CQDs是否可以重置农药驱动的细胞内稳态障碍 在神经母细胞瘤衍生细胞模型中。在目标3中，我们将测试它们恢复神经元损失和行为缺陷的能力， C. elegans使用易于淀粉样蛋白生成的菌株和/或通过农药暴露。在前一种情况下， 将表达mHTT、淀粉样蛋白β或α-突触核蛋白的人暴露于CQD，而后一个目的通过引入 把CQDs植入杀虫剂攻击的蠕虫体内。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，我们将在生物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减弱农药相关神经元腐败的能力。CQDs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。