Mechanisms of Mast Cell Directed Carbon Nanotube Toxicity

 描述（由申请人提供）：工程纳米材料（ENM）具有独特的物理化学性质，有可能影响社会的各个方面。虽然研究和拟议的应用继续迅速增长，健康和安全的ENMs仍然是一个主要关注的公众以及政策制定者和资助机构。虽然对ENM引起毒性的特性进行了大量研究，但很少有工作关注ENM促进或加剧过敏性疾病的能力。 肥大细胞活化是过敏性疾病发展的核心，一直是许多药物的障碍，并可能对纳米医学构成挑战。因此，关于ENM的健康和安全影响的研究必须解决纳米药物、纳米消费品或职业暴露的潜力，以及对过敏性疾病或潜在过敏性疾病（如哮喘）加重的影响。我们已经确定，通过第一个周期的资助，某些ENM直接（通过清道夫受体B1）或间接（通过IL-33）引起肥大细胞活化，导致不良的肺和心血管结局。基于这些发现，我们已经开始研究ENM促进肥大细胞脱颗粒或IL-33产生的特性。我们的初步数据表明，态密度或电子能级的ENM，作为一个尚未认识到的物理化学性质，有助于肥大细胞脱粒通过电荷转移到细胞表面受体或蛋白质。此外，通过初步研究，我们发现肥大细胞对ENM的反应在近交系小鼠之间存在显著差异，表明这些反应本质上是多基因的。对于这个项目，我们假设ENM指导的肥大细胞活化是由纳米生物界面的关键物理特性和化学过程驱动的，这些物理特性和化学过程启动了新的信号传导途径，与其他病原体/散装过敏原不同，由清道夫受体B1驱动，这种反应在很大程度上受遗传学影响。我们的目标是：1）通过使用ENM的组合文库来确定负责肥大细胞活化的ENM的物理化学性质; 2）通过细胞信号传导研究来建立在肥大细胞对ENM的应答中通过清道夫受体B1介导的新信号传导途径的贡献;第三章利用杂交小鼠的全基因组关联分析和转录组学，阐明遗传学在肥大细胞对ENM暴露的反应中的作用近交系和重组近交系的多样性组。了解这些机制将使我们能够设计更好的模型和体外筛选工具来预测ENM毒性，这对风险评估将是重要的。更重要的是，通过更深入地了解导致肥大细胞脱粒的物理化学性质，我们将能够设计材料来防止肥大细胞反应。

 DESCRIPTION (provided by applicant): Engineered nanomaterials (ENMs) have unique physicochemical properties with potential to impact diverse aspects of society. While the research and proposed applications of ENMs continue to grow rapidly, the health and safety of ENMs still remains a major concern to the public as well as to policy makers and funding agencies. While there has been considerable investigation into the properties of ENMs that elicit toxicity, little work has focused on the ability of ENMs to promote or exacerbate allergic disease. Mast cell activation, which is central to development of allergic disease, has been an impediment to a number of pharmaceuticals and will likely represent a challenge for nanomedicines. Consequently, research on the health and safety implications of ENMs must address the potential for nanomedicines, nano-based consumer products or occupational exposures and the impact on initiation of allergic disease or exacerbation of underlying allergic diseases such as asthma. We have established, through the first cycle of this grant, that certain ENMs elicit mast cell activation either directly (via scavenger receptor B1) or indirectly (via IL-33) leading to adverse pulmonary and cardiovascular outcomes. Based on these findings, we have begun to investigate the properties of ENMs that promote mast cell degranulation or IL-33 production. Our preliminary data has suggested that the density of states or electronic energy levels of the ENM, as a yet unrecognized physicochemical property, contribute to mast cell degranulation through charge transfer to cell surface receptors or proteins. In addition, through preliminary studies, we have found that mast cell responses to ENMs are significantly variable across strains of inbred mice suggesting these responses are polygenic in nature. For this project, we hypothesize that ENM-directed mast cell activation is driven by key physical properties and chemical process at the nano-bio interface, which initiate novel signaling pathways, distinct from other pathogens/bulk allergens, driven by scavenger receptor B1 and this response is largely influenced by genetics. Our objectives are: 1) determine the ENM physicochemical properties responsible for mast cell activation through use of combinatorial library of ENMs; 2) establish the contribution of novel signaling pathways mediated through scavenger receptor B1 in the mast cell response to ENMs through cellular signaling studies; 3) elucidate the role of genetics in mast cell responses to ENM exposure using genome wide association analysis and transcriptomics with a hybrid mouse diversity panel of inbred and recombinant inbred strains. Understanding these mechanisms will allow us to design better models and in vitro screening tools to predict ENM toxicity, which will be important for risk assessment. More importantly, by gaining a more in depth understanding of the physicochemical properties that lead to mast cell degranulation, we will be able to engineer materials to prevent mast cell responses.