Dietary DHA attenuation of nanoparticle inflammation

膳食 DHA 减轻纳米颗粒炎症

基本信息

批准号：
9164796
负责人：
Andrij Holian
金额：
$ 10万
依托单位：
UNIVERSITY OF MONTANA
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

来源：
https://reporter.nih.gov/project-details/9164796
关键词：
Acute Address Affect Autophagocytosis Biological Carbon Nanotubes Cathepsins B Cell Membrane Permeability Characteristics Chemicals Chemistry Cholesterol Development Diet Electronics Event Exposure to Goals Growth Guidelines Health Human In Vitro Industry Inflammation Inflammatory Inflammatory Response Inhalation Toxicology Interleukin-1 Knowledge Libraries Link Lung Lung Inflammation Mesothelioma Metals Modification Morphology Mus Outcome Pathology Pattern Play Production Property Public Health Pulmonary Fibrosis Regulation Research Role Safety Structure-Activity Relationship Surface Testing Toxic effect Variant attenuation base chemical property cholesterol trafficking design hazard improved in vivo insight interest multi walled carbon nanotube nanomaterials nanoparticle nanotoxicology oxidant stress particle physical property response single walled carbon nanotube uptake

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引起肺部炎症和纤维化，但造成这些影响的机制尚不清楚。此外，制造多种不同形式的碳纳米管 (CNT) 的能力使得迫切需要更好地了解 CNT 安全性和危害等级。我们已经描述了 CNT 激活会导致吞噬溶酶体膜通透性 (LMP)，从而导致组织蛋白酶 B 的释放和 NLRP3 炎性体激活。然而，导致 LMP 和控制炎症反应（例如自噬）的其他事件的机制尚未得到很好的描述，从而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征良好的库具有受控特性（物理和化学）的多壁和单壁碳纳米管，代表了最具商业可行性的形式，并使用这些材料来深入了解碳纳米管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 的特定特性，而这些特性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而导致 LMP。因此，我们建议我们能够根据这些特性预测 CNT 的促炎和促纤维化活性。中心假设将通过以下目标进行测试：目标 1：开发具有特定物理化学特性的完全表征的 CNT 的综合库。目标 2：确定目标 1 中开发的 CNT 生物活性机制，并表征 CNT 引起 LMP、NLRP3 激活（IL-1？释放）和自噬的摄取和相对生物活性。目标 3：评估所选 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碳纳米管物理化学性质的毒性预测方法。该策略可用于危险排名以及具有高商业潜力的碳纳米管形式的安全设计。