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.
由于微米级颗粒暴露(如二氧化硅、石棉等)导致的肺部和全身疾病
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)
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Andrij Holian其他文献
Andrij Holian的其他文献
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{{ 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:
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