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: 10683961
• 负责人: Christopher K Glass
• 金额: $ 249.25万
• 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/10683961
• 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; Fibroblast Growth Factor; Fibrosis; 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; Macrophage; Magnetic Resonance Imaging; Malondialdehyde; Massive Parallel Sequencing; Measurement; Measures; Mediating; Metabolism; Mus; Obesity; Outcome; Participant; Patients; Phenotype; Phospholipids; Population; Process; Protons; Receptor Cross-Talk; Risk; Risk Factors; Role; Sampling; Signal Transduction; Statistical Data Interpretation; Techniques; Testing; Therapeutic; Tissues; adduct; biomarker performance; cardiovascular disorder risk; cardiovascular risk factor; cohort; coronary calcium scoring; cytokine; density; disease phenotype; effective therapy; elastography; human disease; human subject; lipid biosynthesis; lipidomics; 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.

项目摘要 全面的 尽管发展了越来越有效的疗法以降低升高的动脉粥样硬化脂蛋白水平，但 心血管疾病（CVD）并发症预计将在全球范围内增加，部分原因是增加 肥胖和胰岛素抵抗的发生率。一个紧急问题是非酒精脂肪肝的程度 疾病（NAFLD），它是从脂肪肝脏到非酒精性脂肪性肝炎（NASH）再到肝硬化的频谱 有助于CVD风险。在患有NAFLD的患者中，死亡的主要原因是CVD，据估计 对于总死亡率的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，而另一些则影响疾病 过程。我们PPG的总体假设是肝脂肪和纤维化预测CVD风险，并且 靶向巨噬细胞中肝脏X受体（LXR）的干预措施，肠道中的Farnesyl X受体（FXR）和 肝脏和动脉壁中的氧化特异性表位（OS）将揭示有助于 NASH和CVD之间的临床关联。重要的是，这些干预措施中的每一个都利用 代表性的小分子或抗体具有临床试验的潜力。识别 已知和未知风险因素促进NASH和CVD的机制将非常重要 意义，尤其是针对其中一种或多种机制会对这两者产生有益的影响 疾病。为了实现这一目标，我们提出了一个PPG，该PPG由四个高度相互关联的项目和三个核心组成。 克里斯托弗·格拉斯（Christopher Glass）领导的项目1将检验以下假设，即巨噬细胞中LXR的选择性激活 甲状腺素模拟物的库普弗细胞将导致动脉粥样硬化和纳什的减少，而不会引起 脂肪变性或高甘油三酸酯血症。由罗纳德·埃文斯（Ronald Evans）博士领导的项目2将调查以下假设。 FXR在肠道或肝脏中的选择性激活将导致动脉粥样硬化和NASH的减少。项目3， 由约瑟夫·维兹图姆（Joseph Witztum）博士领导，将检验以下假设，即抗体介导的OS中的降低将进行协调 减少动脉粥样硬化和纳什。由Rohit Loomba博士领导的项目4将调查 肝脂肪含量和纤维化具有人类受试者的心血管风险，并启用转化延伸 项目1、2和3中提出的机械发现。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 来自相关样品的靶向脂肪组谱和细胞因子水平。基因组学和生物信息学核心 将支持项目1，2的大规模基于测序的测定（例如RNA SEQ）的应用 和3，并为生物信息学和统计分析提供了共享资源。行政核心将 支持PPG的整体行政和科学需求。