Nano-Antioxidants as a Therapeutic for Preclinical Models of NAFLD

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)包括一系列的肝脏疾病，从单纯性脂肪变性(肝脏中的脂肪)到非酒精性脂肪性肝炎(NASH)到肝硬变。根据国家糖尿病、消化和肾脏疾病研究所(NIDDK)的数据，它是最常见的慢性肝病形式，随着肥胖、糖尿病和代谢综合征的风险因素不断上升，NAFLD的患病率预计也将增加。虽然氧化应激在NAFLD中的作用已被接受，但尚不清楚的是在NAFLD的临床前模型中降低氧化应激的有效性。如果没有这些知识，我们就无法确定新型高效抗氧化剂作为治疗NAFLD损伤的潜在疗法的效用。为了开发NAFLD的抗氧化剂，这种抗氧化剂显示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，我们转向了纳米技术。这些纳米抗氧化剂，聚乙二醇化亲水碳簇(PEGHCs)，是基于碳纳米结构，具有共轭环结构，因此它们作为末端氧化剂受体或自由基海绵。我们还证明了这些聚乙二醇-羟基喜树碱可以靶向于特定的细胞类型(手稿正在准备中)。我们的长期目标是了解活性氧物种(ROS)在NAFLD病理中的作用机制，以开发有效的治疗方法来预防和潜在地逆转氧化应激造成的损伤。本研究的目的是通过对NAFLD小鼠模型的体内成像、生化和组织病理学研究，确定通过新型高效抗氧化剂降低ROS对NAFLD病理发展的影响。我们的中心假设是，降低ROS将改善NAFLD小鼠模型的肝功能，减少肝脏损伤和氧化应激。这项拟议工作的基本原理是，从机理上理解氧化应激对NAFLD病理的影响将为可行的治疗方法奠定基础。 公共卫生相关性：拟议的研究与公共健康相关，因为我们正在进行的研究将促进我们对氧化应激在非酒精性脂肪性肝病(NAFLD)发展中的作用的理解。因此，拟议的工作与NIH开发新的创新方法来治疗NAFLD的使命的组成部分相关，NAFLD是一种正在上升的疾病，具有重大的健康后果。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because we are conducting research that will advance our understanding of the role of oxidative stress in the development of non-alcoholic fatty liver disease (NAFLD). As a result, the proposed work is relevant to the component of NIH's mission of developing novel and innovative methods to treat NAFLD, a disease that is on the rise and has significant health consequences.