Role of particle surface functionalization in inflammation
颗粒表面功能化在炎症中的作用
基本信息
- 批准号:10810001
- 负责人:
- 金额:$ 5.4万
- 依托单位:
- 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:2022-05-05 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AerosolsAffectAlveolar MacrophagesAnimal ModelApplied ResearchAsbestosBiologicalBiological ModelsCASP1 geneCell Membrane PermeabilityCell physiologyCellsCharacteristicsChargeChemistryCholesterolDevelopmentDiseaseDustEngineeringEventExposure toGoalsHealthIL18 geneImmuneIn VitroIndustrializationInflammasomeInflammationInflammatoryInhalationInjuryInterleukin-1 betaKnockout MiceKnowledgeLibrariesLung diseasesLysosomesMacrophageMediatingMembraneMitochondriaModelingNanosphereNanotechnologyOccupationalOutcomeParticle SizePathologyPathway interactionsPeptide HydrolasesPhagolysosomePhagosomesPharmaceutical PreparationsPhenotypePreparationProcessPropertyPulmonary FibrosisPulmonary InflammationPulmonary PathologyResearchResolutionRoleSignal TransductionSilicatesSilicon DioxideSurfaceSurface PropertiesSystemic diseaseTestingTherapeuticTherapeutic InterventionToxic effectUncertaintyVesicleWettabilityamphiphilicitybafilomycin Acommercial applicationcytokinecytotoxicitydesignexposed human populationfundamental researchgranitehazardin vivointerestlarge-conductance calcium-activated potassium channelslysosome membranemetal oxidenanoengineeringnanomaterialsnanotoxicologynovel therapeuticsparticleparticle exposurepaxillinepreventresponsetherapeutic developmenttherapeutically effectivetitanium dioxidewater solubility
项目摘要
Lung and systemic diseases as a result of micron-sized particle exposures (e.g., silica, asbestos, and more
recently, dusts from preparation of granite countertops) are a critical health problem in the US and around the
world. Unfortunately, these diseases remain untreatable in part due to lack of information on the mechanisms of
injury and inflammation. To date, extensive research that has failed to identify the key steps with potential for
therapeutic intervention. Adding to the potential problems of the above particle exposures, there are growing
concerns that the increased use of engineered nanomaterials (ENM) will add to the burden of lung and systemic
diseases in humans exposed in environmental and occupational settings to these new materials. We know that
the physicochemical characteristics of ENM play a role in toxicity and hazard potential. Therefore, there is a
critical need to understand how specific physicochemical properties of ENM (e.g., surface chemistry, charge and
wettability) affect cell function and in vivo inflammatory outcomes. Furthermore, although MeO ENM have been
shown to cause inflammation, leading to lung fibrosis, the precise mechanisms of ENM-induced inflammation
remain unclear. We have demonstrated that ENM cause phagolysosomal membrane permeability (LMP), leading
to release of lysosomal proteases, which have been implicated in downstream effects such as NLRP3
inflammasome activation, and mitochondrial damage in alveolar macrophages, and significantly contribute to in
vivo inflammation and pathology. However, the mechanisms responsible for LMP, which we proposed to be the
key rate-limiting effect of ENM and silica toxicity, remain unknown. This uncertainty impedes the progress in the
field of particle-induced inflammation and nanotoxicology and limits the ability to develop targeted treatments for
adverse health effects. Our central hypothesis is that the relative biological activity of ENM and silica is
dependent on specific surface properties that define particle-phagolysosome membrane interactions leading to
LMP. Furthermore, we postulate that ENM and silica interact with the interior of the phagolysosomal membrane
leading to K+ flux through the BK channel and membrane hyperpolarization causing LMP and initiate the
inflammatory pathway described in our model. The following aims will test our central hypothesis and accomplish
our goals: 1: Synthesize and characterize MeO ENM with specific physicochemical properties.; 2: Determine the
mechanism of MeO-induced LMP leading to toxicity and NLRP3 inflammasome activation and the relationship
between ENM surface properties and biological activity; and 3: Demonstrate that in vitro MeO ENM-induced
LMP and macrophage responses define in vivo pathology following aerosol exposures to selected MeO ENM. It
is anticipated that these studies will help elucidate the primary mechanism responsible for MeO ENM-mediated
LMP, confirm the central role of LMP in macrophage response to ENM as well as in inflammation and pathology
and test potential therapeutics.
由于暴露于微米级颗粒而导致的肺部和全身性疾病(例如,硅石、石棉等
最近,在美国和世界各地,
世界不幸的是,这些疾病仍然无法治疗,部分原因是缺乏关于这些疾病的机制的信息。
损伤和炎症。迄今为止,广泛的研究未能确定有可能实现这一目标的关键步骤。
治疗干预除了上述颗粒暴露的潜在问题外,
担心工程纳米材料(ENM)的使用增加将增加肺部和全身的负担,
在环境和职业环境中暴露于这些新材料的人类疾病。我们知道
环境纳米材料的物理化学特性在毒性和潜在危害方面发挥作用。因此有
迫切需要了解ENM的具体物理化学性质(例如,表面化学、电荷和
润湿性)影响细胞功能和体内炎症结果。此外,虽然MEO ENM已被
显示引起炎症,导致肺纤维化,ENM诱导炎症的确切机制
仍然不清楚。我们已经证明,ENM引起吞噬溶酶体膜通透性(LMP),导致
溶酶体蛋白酶的释放,这与下游效应有关,如NLRP 3
炎性小体活化和肺泡巨噬细胞中的线粒体损伤,并显著促进炎症反应。
体内炎症和病理学。然而,负责LMP的机制,我们建议是
ENM关键限速作用和二氧化硅毒性仍然未知。这种不确定性阻碍了
颗粒诱导的炎症和纳米毒理学领域,并限制了开发针对性治疗的能力,
对健康的不良影响。我们的中心假设是ENM和二氧化硅的相对生物活性是
依赖于限定颗粒-吞噬溶酶体膜相互作用的特定表面性质,
进出口股份此外,我们假设ENM和二氧化硅与吞噬溶酶体膜的内部相互作用
导致K+通量通过BK通道和膜超极化,引起LMP,并启动
在我们的模型中描述的炎症通路。以下目标将检验我们的中心假设,并实现
我们的目标:1:合成并表征具有特定理化性质的MeO ENM。2:确定
MeO诱导的LMP导致毒性和NLRP 3炎性小体激活的机制及其关系
ENM表面性质和生物活性之间的关系;以及3:证明体外MeO ENM诱导的
LMP和巨噬细胞反应定义了气溶胶暴露于选定的MeO ENM后的体内病理学。它
预计这些研究将有助于阐明负责MeO ENM介导的主要机制
LMP,证实了LMP在巨噬细胞对ENM的反应以及炎症和病理学中的中心作用
测试潜在的治疗方法
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Andrij Holian其他文献
Andrij Holian的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Andrij Holian', 18)}}的其他基金
Improving middle grade STEM interest and increased learning using GN and DOC
使用 GN 和 DOC 提高中年级 STEM 兴趣并增加学习
- 批准号:
10665328 - 财政年份:2023
- 资助金额:
$ 5.4万 - 项目类别:
Lysosomal BK channel regulates cSiO2-induced macrophage inflammation
溶酶体 BK 通道调节 cSiO2 诱导的巨噬细胞炎症
- 批准号:
10618324 - 财政年份:2022
- 资助金额:
$ 5.4万 - 项目类别:
Role of particle surface functionalization in inflammation
颗粒表面功能化在炎症中的作用
- 批准号:
10618289 - 财政年份:2022
- 资助金额:
$ 5.4万 - 项目类别:
Role of particle surface functionalization in inflammation
颗粒表面功能化在炎症中的作用
- 批准号:
10714399 - 财政年份:2022
- 资助金额:
$ 5.4万 - 项目类别:
Role of particle surface functionalization in inflammation
颗粒表面功能化在炎症中的作用
- 批准号:
10463190 - 财政年份:2022
- 资助金额:
$ 5.4万 - 项目类别:
Lysosomal BK channel regulates cSiO2-induced macrophage inflammation
溶酶体 BK 通道调节 cSiO2 诱导的巨噬细胞炎症
- 批准号:
10463030 - 财政年份:2022
- 资助金额:
$ 5.4万 - 项目类别:
Differential responses of males and females to multi-walled carbon nanotubes
男性和女性对多壁碳纳米管的不同反应
- 批准号:
10266754 - 财政年份:2020
- 资助金额:
$ 5.4万 - 项目类别:
Differential responses of males and females to multi-walled carbon nanotubes
男性和女性对多壁碳纳米管的不同反应
- 批准号:
9912608 - 财政年份:2020
- 资助金额:
$ 5.4万 - 项目类别:
Dietary DHA attenuation of nanoparticle inflammation
膳食 DHA 减轻纳米颗粒炎症
- 批准号:
9164796 - 财政年份:2014
- 资助金额:
$ 5.4万 - 项目类别:
Bioactivity and mechanistic studies using a comprehensive and well characterized
使用全面且特征明确的方法进行生物活性和机制研究
- 批准号:
8894506 - 财政年份:2014
- 资助金额:
$ 5.4万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 5.4万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 5.4万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 5.4万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 5.4万 - 项目类别:
Studentship