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：
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
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

来源：
https://reporter.nih.gov/project-details/10669598
关键词：
Acids Address Agriculture Alzheimer&apos 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

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.

接触农药、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。环境和家庭使用鱼藤酮、代森锰、百草枯、环丙环胺等农药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神经元中淀粉样蛋白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) 努力限制环境毒物驱动的疾病。用小分子来治疗神经退行性疾病取得了有限的成功，我们在此探讨是否有一种新的药物。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，例如它们通过绿色化学技术去除果皮、废纸和有机酸，并且具有低细胞毒性。重要的是，它们可以进行化学功能化和掺杂，当进行化学调整时，它们可以找到应用。我们实验室的初步数据显示，它可用于生物传感、组织成像、药物输送。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。我们认为 CQD 可以改善环境毒害，并保护它们免受百草枯毒性。我们通过确定 CQD 是否可以干预淀粉样蛋白来检验目标 1 中的这一假设。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。在目标 2 中，使用许多蛋白质组和原纤维等中间体来钝化它们。神经代谢组学读数，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。线虫使用易于淀粉样蛋白生成和/或通过农药暴露的菌株。在前一种情况下，蠕虫菌株。表达 mHTT、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通过定量关联淀粉样蛋白聚集和运动损害，将 CQD 转化为受农药挑战的蠕虫。 CQD 类型和剂量，我们将在生物学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 减轻农药相关的 CQD 的能力。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。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Screening Carbon Nano Materials for preventing amyloid protein aggregation by adopting a facile method.

采用简便方法筛选防止淀粉样蛋白聚集的碳纳米材料。

DOI：
发表时间：
2024-03-29
期刊：
影响因子：
0
作者：
Wilson, Daisy L;Carreon, Ana;Chinnam, Sampath;Sharifan, Hamidreza;Ahlawat, Jyoti;Narayan, Mahesh
通讯作者：
Narayan, Mahesh