A Cardiovascular-NASH disease nexus: Common Mechanisms and Treatments?

心血管疾病与 NASH 疾病的关系：常见机制和治疗方法？

• 批准号: 10262913
• 负责人: Christopher K Glass
• 金额: $ 252.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262913
• 关键词: Acetaldehyde; Affect; Antibodies; Arteries; Atherosclerosis; Bioinformatics; Bioinformatics Shared Resource; Biological Assay; Biological Markers; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cirrhosis; Clinical; Clinical Trials; Cohort Studies; Collaborations; Collagen; Desmosterol; Development; Disease; Doctor of Philosophy; Environmental Risk Factor; Epigenetic Process; Epitopes; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gap Junctions; Gene Expression Profile; Genetic; Genomics; Glass; Goals; Health; Hepatic; Homeostasis; Human; Hypertriglyceridemia; In Vitro; Incidence; Inflammation; Insulin Resistance; Intervention; Intestines; Kupffer Cells; Lipoproteins; Liver; Liver X Receptor; Lysophosphatidylcholines; Magnetic Resonance Imaging; Malondialdehyde; Massive Parallel Sequencing; Measurement; Measures; Mediating; Metabolism; Mus; Obesity; Outcome; Oxides; Participant; Patients; Phenotype; Phospholipids; Population; Process; Protons; Risk; Risk Factors; Role; Sampling; Signal Transduction; Statistical Data Interpretation; Techniques; Testing; Therapeutic; Tissues; adduct; base; biomarker performance; cardiovascular disorder risk; cardiovascular risk factor; cohort; coronary artery calcium; cytokine; density; disease phenotype; disorder control; effective therapy; elastography; human disease; human subject; lipid biosynthesis; lipidomics; macrophage; mimetics; monocyte; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; peripheral blood; prospective; receptor; receptor function; recruit; small molecule; stable isotope; therapeutic development; transcriptome sequencing

PROJECT SUMMARY Overall Despite the development of increasingly effective therapies to reduce elevated levels of atherogenic lipoproteins, cardiovascular disease (CVD) complications are projected to rise worldwide due in part to the increasing incidence of obesity and insulin resistance. An emergent question is the extent to which non-alcoholic fatty liver disease (NAFLD), which is a spectrum ranging from fatty liver to non-alcoholic steatohepatitis (NASH) to cirrhosis, contributes to CVD risk. Among patients with NAFLD, the leading cause of death is CVD, estimated to account for 31% of total mortality. The development of NAFLD and cardiovascular disease is influenced by combinations of genetic and environmental factors, some of which are disease-specific and others that affect both disease processes. The overall hypotheses of our PPG are that liver fat and fibrosis predict CVD risk and that interventions targeting Liver X receptors (LXRs) in macrophages, the farnesyl X receptor (FXR) in the gut, and oxidation specific epitopes (OSEs) in the liver and artery wall will reveal common mechanisms that contribute to the clinical association between NASH and CVD. Importantly, each of these interventions make use of representative small molecules or antibodies that have the potential to be advanced for clinical trials. Identifying mechanisms by which known and unknown risk factors promote both NASH and CVD would be of great significance, especially if targeting one or more of these mechanisms would produce beneficial effects on both diseases. To achieve this goal, we propose a PPG consisting of four highly inter-related projects and three cores. Project 1, led by Dr. Christopher Glass, will test the hypothesis that selective activation of LXRs in macrophages and Kupffer cells with desmosterol mimetics will result in reductions of atherosclerosis and NASH without causing steatosis or hypertriglyceridemia. Project 2, led by Dr. Ronald Evans, will investigate the hypothesis that selective activation of FXR in the gut or liver will result in reductions in atherosclerosis and NASH. Project 3, led by Dr. Joseph Witztum, will test the hypothesis that antibody-mediated reductions in OSEs will coordinately reduce both atherosclerosis and NASH. Project 4, led by Dr. Rohit Loomba, will investigate the relationships of liver fat content and fibrosis with cardiovascular risk in human subjects and enable translational extension of mechanistic findings made in Projects 1, 2 and 3. A Phenotyping Core will enable Projects 1, 2 and 3 to quantitatively evaluate extent of atherosclerosis and NASH in mouse models, and enable all projects to obtain targeted lipidomic profiles and cytokine levels from relevant samples. A Genomics and Bioinformatics Core will support the application of massively parallel sequencing-based assays, such as RNA Seq, by Projects 1, 2 and 3 and provide a shared resource for bioinformatics and statistical analysis. An Administrative Core will support the overall administrative and scientific needs of the PPG.

项目概要 全面的 尽管开发了越来越有效的疗法来降低致动脉粥样硬化脂蛋白的升高水平， 预计全球心血管疾病 (CVD) 并发症将会增加，部分原因是心血管疾病 (CVD) 并发症的增加 肥胖和胰岛素抵抗的发生率。一个紧迫的问题是非酒精性脂肪肝的程度 疾病（NAFLD），范围从脂肪肝到非酒精性脂肪性肝炎（NASH）再到肝硬化， 增加 CVD 风险。在 NAFLD 患者中，CVD 是导致死亡的主要原因，据估计 占总死亡率的 31%。 NAFLD 和心血管疾病的发展受到组合的影响 遗传和环境因素，其中一些是疾病特异性的，另一些则影响两种疾病 流程。我们 PPG 的总体假设是肝脏脂肪和纤维化可预测 CVD 风险，并且 针对巨噬细胞中的肝脏 X 受体 (LXR)、肠道中的法尼基 X 受体 (FXR) 的干预措施，以及 肝脏和动脉壁中的氧化特异性表位（OSE）将揭示有助于 NASH 和 CVD 之间的临床关联。重要的是，每项干预措施都利用了 有潜力进行临床试验的代表性小分子或抗体。识别 已知和未知的危险因素促进 NASH 和 CVD 的机制将非常重要 意义重大，特别是如果针对这些机制中的一种或多种会对双方产生有益的影响 疾病。为了实现这一目标，我们提出了一个由四个高度相关的项目和三个核心组成的 PPG。 项目 1 由 Christopher Glass 博士领导，将测试巨噬细胞中 LXR 选择性激活的假设 和库普弗细胞与去莫甾醇模拟物将导致动脉粥样硬化和 NASH 的减少，而不会引起 脂肪变性或高甘油三酯血症。项目 2 由 Ronald Evans 博士领导，将研究以下假设： 选择性激活肠道或肝脏中的 FXR 将减少动脉粥样硬化和 NASH。项目3， 由 Joseph Witztum 博士领导，将测试抗体介导的 OSE 减少将协调的假设 减少动脉粥样硬化和 NASH。项目 4 由 Rohit Loomba 博士领导，将调查 人类受试者的肝脏脂肪含量和纤维化与心血管风险相关，并能够转化延伸 项目 1、2 和 3 中的机制发现。表型核心将使项目 1、2 和 3 定量评估小鼠模型中动脉粥样硬化和 NASH 的程度，并使所有项目能够获得 相关样本的目标脂质组学特征和细胞因子水平。基因组学和生物信息学核心 将支持项目 1、2 的大规模并行测序分析的应用，例如 RNA Seq 3并为生物信息学和统计分析提供共享资源。行政核心将 支持 PPG 的整体管理和科学需求。