Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury

治疗创伤性脑损伤的新型碳纳米酶机制

• 批准号: 10598021
• 负责人: Muralidhar L Hegde
• 金额: $ 46.1万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598021
• 关键词: Activated Charcoal; Acute; Acute Brain Injuries; Address; Aging; Antioxidants; Binding Sites; Blood - brain barrier anatomy; Brain Injuries; Carbon; Carbon nanoparticle; Cell Aging; Cells; Characteristics; Chelating Agents; Chemicals; Chronic Disease; Clinic; Coal; Complex; Contusions; DNA Damage; DNA Double Strand Break; Deferoxamine; Disease; Electron Transport; Environment; Enzymes; Ethylenes; Event; Free Radicals; Funding; Generations; Genomics; Glycols; Goals; Good Manufacturing Process; Hemin; Hemoglobin; Hemorrhage; Human; Impaired cognition; In Vitro; Inflammation; Injury; Iron; Iron Chelation; Learning; Lesion; Link; Materials Testing; Mediator; Mitochondria; Modeling; Nature; Nervous System Physiology; Neurons; Nuclear Accidents; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Quantum Dots; Quinones; Resistance; Rodent; Role; Site; Source; Speed; Superoxide Dismutase; Testing; Therapeutic; Therapeutic Uses; Tissues; Toxic effect; Traumatic Brain Injury; Work; carboxylate; carboxylation; covalent bond; design; disability; functional decline; functional outcomes; functional restoration; graphene; hydrophilicity; improved; in vivo; in vivo Model; lead candidate; mild traumatic brain injury; mimetics; mitochondrial dysfunction; nanomaterials; nanoparticle; new therapeutic target; novel; novel therapeutics; oxidative damage; particle; prevent; response; senescence

Abstract: In the prior funding cycle, we successfully obtained a mechanistic understanding of the chemical basis for the excellent therapeutic actions in mild traumatic brain injury (TBI) of our carbon nanoparticle (CNP) platform, poly(ethylene)glycol-hydrophilic carbon clusters (PEG-HCCs). We identified new actions that point to profound new directions for our CNPs. We: 1) discovered that the HCC's broad redox potential extended their action as a redox mediator among mitochondrial constituents involved in electron transport, i.e. a nanoparticle enzyme, or “nanozyme”, and 2) identified a new mechanism by which hemorrhage causes cellular toxicity: rapid and persistent generation of DNA double strand breaks and robust DNA damage response leading to cellular “senescence”, in which cells become a nidus for inflammation. While senescence could be prevented by PEG- HCCs, the cells became sensitized to iron toxicity/ferroptosis. This interaction led us to generate a new CNP, covalently bonding iron chelator, deferoxamine (DEF). Our results indicate DEF-HCC-PEG effectively addressed hemin and iron-related injury, senescence and ferroptosis. Given that mitochondrial dysfunction and hemorrhagic contusion (HC) are associated with poor outcome in TBI, these findings directly indicate the benefit of pursuing these mechanisms. The identification of key mechanistic features of our CNP platform that facilitate a mitochondrial site of action and new mechanism of hemorrhage-induced pathology form the basis for this renewal application. We will incorporate our understanding of the PEG-HCC mechanisms of action to generate a more immediately translatable CNP utilizing a good manufacturing practice (GMP) starting material, activated charcoal, and test them in-vivo in a rodent TBI with hemorrhagic contusion (TBI/HC). Our overall hypothesis is that the mechanisms of action discovered in our prior application will be translatable to GMP starting materials and will act on both the genomic and mitochondrial damage associated with TBI/HC. Specific Aim 1 will test the hypothesis that an oxidizing synthesis environment can be optimized to generate GMP-derived starting materials, PEG-oxidized activated charcoal achieving, the desired characteristics of a CNP nanozyme. Specific Aim 2 will test the hypothesis that DEF-linked CNP will address hemorrhage-related mitochondrial and genomic events triggering senescence and resistance to ferroptosis. Specific Aim 3 will administer the CNPs developed in Aims 1 and 2 to moderate-severe TBI/HC model. Completion of these Aims will yield a more readily translatable version of our CNP platform building on a growing understanding of the critical features and sites of action for their nanozyme mechanisms. New therapeutic targets emerging from a more thorough understanding of pathological mechanisms by which hemorrhage complicates outcome from TBI will guide the design. By employing GMP starting material, this project can generate breakthrough materials more rapidly translatable to the clinic. Because mitochondrial dysfunction and the cellular consequence of hemorrhage are features both of acute injury and of aging and cognitive decline, a broader potential for this therapy is suggested.

摘要：在先前的资金周期中，我们成功获得了对化学基础的机械理解 对于我们碳纳米颗粒（CNP）平台轻度创伤性脑损伤（TBI）的出色治疗作用， 聚（乙烯）甘油 - 综合碳簇（PEG-HCC）。 我们的CNP的新方向。 涉及电子传输的米氏征服中的氧化还原介体，即纳米颗粒酶 “纳米酶”，2）确定了一种新机制，通过该机制引起细胞毒性：快速和 DNA双链断裂的持续产生和强大的DNA损伤响应导致细胞 “衰老”，其中细胞成为侵蚀的nidus。 HCC，细胞对铁毒/铁肉芽毒素的敏感。 共价粘合铁螯合剂，脱氧胺（DEF）。 解决了hemin和与铁相关的损伤，衰老和铁毒性造成病。 出血挫伤（HC）与TBI的结果不佳有关，这些发现直接起诉了益处 追求这些机制。 线粒体的作用部位和出血诱导的病理学的新机制构成了这一点的基础。 续签应用。 使用良好的制造实践（GMP）的起始材料，更适当地翻译的CNP，激活 木炭和带有出血性挫伤的啮齿动物TBI中的木炭（TBI/HC） 是在我们先前的应用中发现的动作机制将被转换为GMP的起始产业 并将对与TBI/HC相关的基因组和线粒体损伤作用。 假设可以优化氧化合成环境以产生GMP衍生的启动 材料，PEG氧化活化的木炭实现，是CNP纳米酶的所需特征。 AIM 2将检验以下假设：DEF连锁的CNP将解决与出血有关的线粒体和基因组 触发衰老和抗铁毒性的事件。 在AIM 1和2中至中度分数TBI/HC模型。 我们的CNP平台的可翻译版本构建了人们对关键特征和位置的越来越多的理解 纳米机制的作用。 出血使TBI结果复杂化的病理机制将指导设计。 该项目采用GMP起始材料，可以更快地翻译成突破性的材料 诊所。 急性损伤以及衰老和认知能力下降，这是更广泛的潜力。