Predicting the Toxicity of Nanomaterials by a Transforming Protein Corona

工程纳米材料具有独特的电学、机械和物理化学性质 有潜力造福我们的社会。然而，纳米材料的健康和安全性 最近成为公众、政策制定者和监管机构的极大关注。等 由于纳米材料在食品、化妆品、医药 建筑业、制造业和环境。 最近已经确定，纳米材料一旦进入血液或肺部， 表现出与蛋白质、肽、脂质和氨基酸物理吸附的天然倾向 使蛋白质“冠”，可能决定生物利用度和纳米材料的分布， 在宿主系统内，在细胞、组织和生物体水平上。因此， 本申请描述了纳米颗粒-蛋白质冠在生物学上的动态作用， 对用于安全纳米技术和纳米医学的工程纳米材料的反应。 确定纳米颗粒蛋白质冠的健康和安全影响需要 解决以下基本方面：1）动力学和构象变化， 蛋白质的竞争性结合、拥挤和降解，以及2）蛋白质的识别 电晕通过细胞受体和免疫反应。这个项目的核心假设是 纳米颗粒-蛋白质冠实体的物理化学性质与 对电晕的生物反应影响其吸收和超敏反应。我们 我将通过追求三个具体目标来验证这一假设：1）理解纳米颗粒蛋白质 相互作用和转化; 2）确定蛋白质的计算机结构和动力学 3）确定纳米颗粒-蛋白质冠对定向细胞粘附的体外影响; 摄取、ER应激和未折叠蛋白反应。这项申请的理由是， 了解纳米颗粒蛋白质冠对细胞识别，摄取和 反应对于预测毒性和开发安全的纳米技术至关重要。另外这款 R15项目预计将有助于培训新一代的科学家， 生物物理学和生物医学的接口，并促进未来NIH的资助机会， 克莱姆森大学和东卡罗莱纳大学。

Engineered nanomaterials have unique electrical, mechanical and physicochemical properties with potential to benefit our society. However, the health and safety of nanomaterials has recently become a great concern to the public, policymakers and regulatory agencies. Such concern is justified due to the vast potential use of nanomaterials in food, cosmetics, medicine, construction, manufacturing, and the environment. It has recently been established that nanomaterials, upon entry into the bloodstream or lung, exhibit a natural tendency of physical adsorption with proteins, peptides, lipids and amino acids to render a protein "corona" that may dictate the bioavailability and distribution of nanomaterials within the host system, at the cellular, tissue and organism level. Consequently, the objective of this application is to delineate the dynamic roles of nanoparticle-protein corona on biological responses to engineered nanomaterials for safe nanotechnologies and nanomedicines. Determining the health and safety implications of the nanoparticle-protein corona requires addressing the fundamental aspects of 1) dynamics and conformational changes resulting from competitive binding, crowding and degradation of the proteins, and 2) recognition of the protein corona by cellular receptors and immune responses. The central hypothesis of this project is that the physicochemical properties of the nanoparticle-protein corona entity are correlated with biological responses to the corona to impact on their uptake and hypersensitivity reactions. We will test this hypothesis by pursuing three specific aims: 1) Understand nanoparticle-protein interaction and transformation; 2) Determine the in silico structure and dynamics of protein corona; 3) Determine the in vitro impact of nanoparticle-protein corona on directing cellular uptake, ER stress and the unfolded protein response. The rationale of this application is that understanding the impact of nanoparticle-protein corona on cellular recognition, uptake and response is crucial for predicting toxicity and developing safe nanotechnologies. In addition, this R15 project is expected to contribute to the training of a new generation of scientists at the interface of biophysics and biomedicine and facilitate future NIH funding opportunities for Clemson University and East Carolina University.