Dietary DHA attenuation of nanoparticle inflammation

膳食 DHA 减轻纳米颗粒炎症

• 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
• 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

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）：许多碳纳米管已显示出引起肺部炎症和纤维化，但是对这些作用负责的机制尚不清楚。此外，以许多不同格式生产碳纳米管（CNT）的能力已经迫切地建立了对CNT安全和危害排名的更好理解。我们已经描述了CNT激活引起的吞噬膜膜通透性（LMP），从而释放组织蛋白酶B和NLRP3炎性体激活。但是，造成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。该项目的总体目的是开发良好的图书馆 具有控制性能（物理和化学）的多壁和单壁CNT，代表最可行的形式，并使用这些材料来洞悉机械理解和结构活性在体外和体内的毒性。我们的中心假设是，生物学反应将取决于CNT的特定特性，这些特性调节了吞噬性肿瘤膜通透性（LMP）和自噬。此外，我们建议CNT通过影响胆固醇贩运来引起LMP。因此，我们建议我们能够根据这些特性来预测CNT的促炎和纤维化活性。中央假设将以以下目的进行检验：目标1：建立具有特定理化特征的完全表征的CNT综合库。目标2：确定在AIM 1中开发的CNT生物活性的机制，并表征CNT引起LMP，NLRP3激活（IL-1？释放）和自噬的摄取，相对生物活性。目标3：评估选定CNT体内病理学的机制。我们跨学科团队的长期目标是基于CNT的理化特性开发一种毒性预测的方法。然后，该策略可用于危害排名以及具有较高商业潜力的CNT形式的安全设计。