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
基本信息
- 批准号:10598021
- 负责人:
- 金额:$ 46.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Activated CharcoalAcuteAcute Brain InjuriesAddressAgingAntioxidantsBinding SitesBlood - brain barrier anatomyBrain InjuriesCarbonCarbon nanoparticleCell AgingCellsCharacteristicsChelating AgentsChemicalsChronic DiseaseClinicCoalComplexContusionsDNA DamageDNA Double Strand BreakDeferoxamineDiseaseElectron TransportEnvironmentEnzymesEthylenesEventFree RadicalsFundingGenerationsGenomicsGlycolsGoalsGood Manufacturing ProcessHeminHemoglobinHemorrhageHumanImpaired cognitionIn VitroInflammationInjuryIronIron ChelationLearningLesionLinkMaterials TestingMediatorMitochondriaModelingNatureNervous System PhysiologyNeuronsNuclear AccidentsOutcomeOxidation-ReductionOxidative PhosphorylationPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsPhenotypeQuantum DotsQuinonesResistanceRodentRoleSiteSourceSpeedSuperoxide DismutaseTestingTherapeuticTherapeutic UsesTissuesToxic effectTraumatic Brain InjuryWorkcarboxylatecarboxylationcovalent bonddesigndisabilityfunctional declinefunctional outcomesfunctional restorationgraphenehydrophilicityimprovedin vivoin vivo Modellead candidatemild traumatic brain injurymimeticsmitochondrial dysfunctionnanomaterialsnanoparticlenew therapeutic targetnovelnovel therapeuticsoxidative damageparticlepreventresponsesenescence
项目摘要
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:在之前的资金周期中,我们成功地从机理上理解了化学基础。
对于我们的碳纳米颗粒(CNP)平台对轻度创伤性脑损伤(TBI)的出色治疗作用,
聚乙二醇亲水碳簇(聚乙二醇亲水碳簇)。我们确定了新的行动,这些行动表明
为我们的CNP提供新的方向。我们:1)发现肝细胞癌广泛的氧化还原电势将它们的作用扩展为
参与电子传递的线粒体成分之间的氧化还原媒介,即纳米粒子酶,或
2)确定了出血引起细胞毒性的一种新机制:快速和
持续产生DNA双链断裂和强大的DNA损伤反应导致细胞
“衰老”,即细胞成为炎症的核心。而通过聚乙二醇单抗可以防止衰老-
HCCS后,细胞对铁中毒/铁性下垂敏感。这种相互作用导致我们产生了一个新的CNP,
共价键合铁络合剂去铁胺(DEF)。我们的结果表明DEF-HCC-PEG是有效的
解决了氯化血红素和铁相关的损伤、衰老和铁性下垂。鉴于线粒体功能障碍和
出血性挫伤(HC)与颅脑损伤预后不良有关,这些发现直接表明了其益处。
对这些机制的追求。确定我们的CNP平台的关键机制功能,以促进
线粒体的作用部位和出血病理的新机制构成了这一基础。
续签申请。我们将结合我们对聚乙二醇-肝癌作用机制的理解来生成
使用良好制造规范(GMP)起始材料的更可立即翻译的CNP,已激活
木炭,并在出血性挫伤(TBI/HC)啮齿动物体内测试它们。我们的总体假设
在我们之前的应用中发现的作用机制将可转化为GMP起始材料
并将对与TBI/HC相关的基因组和线粒体损伤起作用。《特定目标1》将测试
假设氧化合成环境可以被优化以产生GMP衍生的起始
材料,聚乙二醇氧化的活性碳,实现了CNP纳米酶的预期特性。特定的
Aim 2将验证DEF连接的CNP将解决出血相关的线粒体和基因组的假设
触发衰老和对铁下垂的抵抗的事件。具体目标3将管理制定的CNP
在AIMS 1和AIMS 2至中-重度颅脑损伤/HC模型中。完成这些目标将更容易产生一个
我们的CNP平台的可翻译版本建立在对关键功能和站点的日益了解的基础上
它们的纳米酶机制的作用。从更彻底的理解中出现新的治疗靶点
出血使脑外伤预后复杂化的病理机制的研究将指导设计。通过
使用GMP起始材料,该项目可以更快地产生可翻译到
诊所。因为线粒体功能障碍和出血的细胞后果都是
在急性损伤、衰老和认知能力下降的情况下,这种疗法的潜力更大。
项目成果
期刊论文数量(0)
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Muralidhar L Hegde其他文献
Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells
哺乳动物细胞中 DNA 碱基切除/单链断裂修复途径的早期步骤
- DOI:
10.1038/cr.2008.8 - 发表时间:
2008-01-01 - 期刊:
- 影响因子:25.900
- 作者:
Muralidhar L Hegde;Tapas K Hazra;Sankar Mitra - 通讯作者:
Sankar Mitra
Muralidhar L Hegde的其他文献
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{{ truncateString('Muralidhar L Hegde', 18)}}的其他基金
Defining the altered FUS-PARP-1-DNA Ligase III axis and its implications to nuclear and mitochondrial genome damage response in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)
定义改变的 FUS-PARP-1-DNA 连接酶 III 轴及其对肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 中核和线粒体基因组损伤反应的影响
- 批准号:
9980670 - 财政年份:2020
- 资助金额:
$ 46.1万 - 项目类别:
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:
9981393 - 财政年份:2015
- 资助金额:
$ 46.1万 - 项目类别:
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:
10397400 - 财政年份:2015
- 资助金额:
$ 46.1万 - 项目类别:
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