Development and testing of Carbon Quantum Dot architectures to arrest neurotoxicant-insult- related outcomes

接触杀虫剂、杀菌剂和除草剂与神经元损伤、神经元丢失以及 神经退行性变。环境和家庭使用的杀虫剂，如鱼藤酮、甘露醇、百草枯、克霉威等 引发线粒体功能障碍。由此导致的活性氧物种(ROS)和活性氮水平的升高 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，如α-突触核蛋白、淀粉样蛋白β和突变体 亨廷顿蛋白(Huntingtin Protein，mHTT)形成有毒的寡聚体和原纤维，在细胞膜上形成毛孔，破坏钙离子 动态平衡，促进神经递质渗漏并引发神经元死亡，导致神经退行性疾病，如 如帕金森氏症(PD)、阿尔茨海默氏症(AD)和亨廷顿氏病(HD)。限制环境毒物驱动的努力 小分子神经退行性病变的治疗效果有限。在这里，我们探索一类新奇的 碳纳米材料，即。碳量子点(CQD)，可以恢复细胞内平衡，防止行为缺陷 在接触杀虫剂的有机体中。CQD很容易从含有生物废弃物的碳前体中合成，例如 用绿色化学技术处理果皮、废纸和有机酸。它们具有较低的细胞毒性，并具有天然的 抗氧化剂。重要的是，它们可以被化学官能化和掺杂。当化学调谐时，它们会找到应用 在生物传感、组织成像、药物输送等方面，可以跨越血脑屏障。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的聚集，减轻细胞内的ROS应激。他们被迷住了。 并保护它们免受百草枯的毒害。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 形成纤维的轨迹。我们还试图扩展我们对功能化的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，以钝化它们。在目标2中，使用了一些蛋白质组和 神经代谢读数，我们确定功能化的CQD是否可以重置农药驱动的细胞代谢紊乱 在神经母细胞瘤来源的模型细胞中。在目标3中，我们将测试他们修复神经元丢失和行为缺陷的能力 使用易发生淀粉样变的菌株和/或通过农药暴露的线虫。在前一种情况下，蠕虫使 表达mHTT、淀粉样蛋白β或α-突触核蛋白的人将暴露在CQD中，而后者的目标是通过引入 CQD进入杀虫剂挑战的蠕虫。通过将淀粉样蛋白聚集和运动性损害与 CQD的类型和剂量，我们将在生物水平上验证我们的假设。拟议工作完成后的调查结果 将定义绿色化学衍生的CQD减轻与农药相关的神经元腐败的能力。CQD是 可能会转化为涉及神经毒性侮辱的脊椎动物(啮齿动物)模型的临床前试验。

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.