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

基本信息

  • 批准号:
    8894506
  • 负责人:
  • 金额:
    $ 50.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Many carbon nanotubes have been shown to cause lung inflammation and fibrosis, but the mechanisms responsible for these effects are not well understood. Furthermore, the ability to manufacture carbon nanotubes (CNT) in many different formats has created an urgency to develop better understanding of CNT safety and hazard ranking. We have described that CNT activated cause phagolysosomal membrane permeability (LMP) leading to release of cathepsin B and NLRP3 inflammasome activation. However, the mechanisms responsible for causing LMP and additional events controlling the inflammatory response (e.g., autophagy) are not well described, thus limiting progress in the field of nanotoxicology. The overall objective of this project is to develop well-characterized libraries of multi-walled and single-walled CNT with controlled properties (physical and chemical) that represent the most commercially viable forms and use these materials to provide insight into a mechanistic understanding and structure activity relationship of CNT toxicity both in vitro and in vivo. Our central hypothesis is that the biological responses will be dependent on specific properties of CNT and these properties regulate phagolysosomal membrane permeability (LMP) and autophagy. Furthermore, we propose that CNT cause LMP by affecting cholesterol trafficking. Therefore, we propose that we will be able to predict the proinflammatory and profibrotic activity of CNT based on these properties. The central hypothesis will be tested with the following aims: Aim 1: Develop a comprehensive library of fully characterized CNT with specific physicochemical characteristics. Aim 2: Determine the mechanism of bioactivity of CNT developed in Aim 1 and characterize the uptake, relative bioactivity of the CNT to cause LMP, NLRP3 activation (IL-1? release) and autophagy. Aim 3: Evaluate the mechanism of in vivo pathology of selected CNT. The long-term goal of our interdisciplinary team is to develop an approach to toxicity prediction based on physicochemical properties of CNT. This strategy can then be used for hazard ranking as well as safe design of the CNT forms with high commercial potential.
描述(由申请人提供):许多碳纳米管已被证明会导致肺部炎症和纤维化,但对这些影响的机制还不清楚。此外,以许多不同形式制造碳纳米管(CNT)的能力已经产生了更好地理解CNT安全性和危害等级的紧迫性。我们已经描述了CNT活化引起吞噬溶酶体膜通透性(LMP),导致组织蛋白酶B的释放和NLRP 3炎性体活化。然而,负责引起LMP和控制炎症反应的其他事件(例如,自噬)没有得到很好的描述,因此限制了纳米毒理学领域的进展。该项目的总体目标是开发特色鲜明的图书馆, 具有受控性质(物理和化学)的多壁和单壁CNT,代表最具商业可行性的形式,并使用这些材料来深入了解CNT体外和体内毒性的机制和结构活性关系。我们的中心假设是,生物反应将取决于CNT的特定性质,这些性质调节吞噬溶酶体膜通透性(LMP)和自噬。此外,我们认为CNT通过影响胆固醇运输引起LMP。因此,我们建议能够根据这些性质预测CNT的促炎症和促纤维化活性。中心假设将测试以下目标:目标1:开发一个全面的图书馆,充分表征碳纳米管与特定的物理化学特性。目标二:确定目标1中开发的CNT的生物活性机制,并表征CNT引起LMP、NLRP 3激活(IL-1?释放)和自噬。目的3:评价所选CNT的体内病理学机制。我们跨学科团队的长期目标是开发一种基于CNT理化性质的毒性预测方法。然后,该策略可用于危险等级以及具有高商业潜力的CNT形式的安全设计。

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:
    $ 50.82万
  • 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:
    10810001
  • 财政年份:
    2022
  • 资助金额:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 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:
    $ 50.82万
  • 项目类别:

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