Mechanisms of mast cell directed carbon nanotube toxicity

 描述(申请人提供)：工程纳米材料(ENM)具有独特的物理化学性质，有可能对社会的各个方面产生影响。尽管环境保护措施的研究和拟议应用继续快速增长，但环境保护措施的健康和安全仍然是公众以及政策制定者和资助机构的主要关切。虽然已经有相当多的研究对ENM的特性引起毒性，但很少有工作集中在ENM促进或加重过敏性疾病的能力上。 肥大细胞激活是过敏性疾病发展的核心，一直是许多药物的障碍，很可能对纳米医学构成挑战。因此，对ENMS的健康和安全影响的研究必须考虑纳米药物、基于纳米的消费品或职业暴露的可能性，以及对引发变态反应疾病或加剧潜在变态反应疾病(如哮喘)的影响。通过这项资助的第一个周期，我们已经确定，某些ENM直接(通过清道夫受体B1)或间接(通过IL-33)诱导肥大细胞激活，从而导致不利的肺和心血管后果。基于这些发现，我们已经开始研究促进肥大细胞脱颗粒或产生IL-33的ENM的特性。我们的初步数据表明，ENM的态密度或电子能级作为一种尚未被认识的物理化学性质，通过向细胞表面受体或蛋白质的电荷转移而促进肥大细胞脱颗粒。此外，通过初步研究，我们发现肥大细胞对ENMS的反应在不同品系的近交系小鼠之间存在显著差异，这表明这些反应本质上是多基因的。在这个项目中，我们假设ENM导向的肥大细胞激活是由纳米生物界面上的关键物理特性和化学过程驱动的，它启动了不同于其他病原体/大宗变应原的新的信号通路，由清道夫受体B1驱动，这种反应在很大程度上受到遗传学的影响。我们的目标是：1)通过使用ENM的组合文库，确定负责肥大细胞激活的ENM的物理化学性质；2)通过细胞信号研究，建立通过清道夫受体B1介导的新的信号通路在肥大细胞对ENM的反应中的贡献；3)利用基因组广泛的关联分析和转录本，以近交系和重组近交系的杂交小鼠多样性小组为基础，阐明遗传学在肥大细胞对ENM暴露的反应中的作用。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的毒性，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颗粒的物理化学性质，我们将能够设计出防止肥大细胞反应的材料。

 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.