Nano-Antioxidants as a Therapeutic for Preclinical Models of NAFLD

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）包括一系列肝脏疾病，从单纯性脂肪变性（肝脏脂肪）到非酒精性脂肪性肝炎（NASH）再到肝硬化。根据美国国家糖尿病、消化和肾脏疾病研究所（NIDDK）的数据，NAFLD是最常见的慢性肝病，随着肥胖、糖尿病和代谢综合征等危险因素的增加，NAFLD的患病率预计也会增加。虽然氧化应激在NAFLD中的作用已被接受，但在临床前NAFLD模型中减少氧化应激的有效性尚不清楚。没有这方面的知识，我们就不能确定新型高效抗氧化剂作为NAFLD损伤的潜在治疗药物的效用。为了开发抗NAFLD的抗氧化剂，这种抗氧化剂表现出强大的抗氧化活性，不会将自由基传递给其他分子，并且可以靶向，我们已经转向纳米技术。这些纳米抗氧化剂，聚乙二醇亲水性碳团簇（peg - hcc），是基于碳纳米结构，具有共轭环结构，因此它们充当末端氧化剂受体或自由基“海绵”。我们还证明了这些peg - hcc可以靶向特定的细胞类型（手稿正在准备中）。我们的长期目标是了解活性氧（ROS）在NAFLD病理中的机制，以便开发有效的治疗方法，预防和潜在地逆转氧化应激造成的损伤。我们的目的是通过NAFLD小鼠模型的体内成像、生物化学和组织病理学来确定高效新型抗氧化剂化合物减少ROS对NAFLD病理发展的影响。我们的中心假设是，在NAFLD小鼠模型中，减少ROS可以改善肝功能，减少肝损伤和氧化应激。这项工作的基本原理是氧化应激对NAFLD病理的机制理解将为可行的治疗方法奠定基础。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, ranging from simple steatosis (fat in the liver) to non-alcoholic steatohepatitis (NASH) to cirrhosis. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), it is the most common form of chronic liver disease and with the risk factors of obesity, diabetes, and metabolic syndrome on the rise, the prevalence of NAFLD is also expected to increase. While the role of oxidative stress in NAFLD is accepted, what is not known is the effectiveness of reducing oxidative stress in preclinical models of NAFLD. Without this knowledge, we cannot determine the utility of novel classes of high- potency antioxidants as potential therapeutics for NAFLD damage. To develop antioxidants for NAFLD that exhibit potent antioxidant activity, that do not pass radicals on to other molecules and that can be targeted, we have turned to nanotechnology. These nano-antioxidants, polyethylene glycolated hydrophilic carbon clusters (PEG-HCCs), are based on carbon nano structures that have conjugated ring structures so that they act as terminal oxidant acceptors or radical "sponges". We have also demonstrated that these PEG-HCCs can be targeted to specific cell types (manuscript in preparation). Our long term goal is to understand the mechanisms of reactive oxygen species (ROS) in NAFLD pathology in order to develop effective therapeutics that can prevent and potentially reverse damage due to oxidative stress. Our objective is to determine the effect of reducing ROS through high-efficiency novel antioxidant compounds on the development of NAFLD pathology by in vivo imaging, biochemistry and histopathology in mouse models of NAFLD. Our central hypothesis is that reducing ROS will improve liver function, reduce liver damage and oxidative stress in mouse models of NAFLD. The rationale for the proposed work is that a mechanistic understanding of oxidative stress on NAFLD pathologies will lay the foundation for viable therapeutic approaches.