Genetic modifiers of atherosclerosis and macrophage phenotypes

总结 心脏病是美国男性和女性的头号杀手。虽然 心血管疾病死亡的发生率有所下降，但仍占每3人中的1人。 死亡动脉粥样硬化引起的冠状动脉疾病（CAD）是其中大部分的原因 死亡尽管对CAD风险因素的了解增加， 但CAD的问题还没有解决。大型人类全基因组关联研究 已经确定了许多与CAD相关的常见遗传变异，但只有一小部分， 遗传风险已经被发现。该提案旨在进行小鼠遗传和 鉴定动脉粥样硬化修饰基因和巨噬细胞遗传修饰基因的基因组研究 泡沫细胞脂滴代谢和炎症，从而深入了解 调节这些途径。拟议研究的第一个目的是确定 负责基因和遗传变异，导致体外巨噬细胞表型， 复杂的遗传和基因编辑方法。拟议研究的第二个目的是 为了在染色体上鉴定的遗传位点中鉴定小鼠动脉粥样硬化修饰基因， 2.这一目标将使用复杂的基因编辑以及更新的小鼠模型， 靶向低密度脂蛋白的反义寡核苷酸治疗诱导的动脉粥样硬化 脂蛋白受体这些发现可能会导致新的药物靶点和治疗，以防止或 治疗冠心病。拟议研究的相关性在于，它们解决了一个重大的健康问题， 关注，冠状动脉疾病，并将产生深入了解的机制，修改 动脉粥样硬化易感性新的途径和蛋白质的发现， 动脉粥样硬化和泡沫细胞胆固醇代谢和炎症提供了新的希望， 风险评估、预防和治疗模式。

Summary Heart disease is the number one killer of men and women in the United States. Although the incidence of cardiovascular disease deaths has declined, it still accounts for ~1 out of every 3 deaths. Coronary artery disease (CAD) due to atherosclerosis was responsible for most of these deaths. Despite increased knowledge about CAD risk factors and the availably of drugs to treat them, the CAD problem has not been solved. Large human genome wide association studies have identified many common genetic variants associated with CAD, but only a small fraction of the heritable risk has been discovered. This proposal aims to perform mouse genetic and genomic studies to identify atherosclerosis modifier genes and genetic modifiers of macrophage foam cell lipid droplet metabolism and inflammation, yielding insights into the mechanisms that regulate these pathways. The first aim of the proposed studies involves identifying the responsible genes and genetic variation that give rise to in vitro macrophage phenotypes using sophisticated genetic and gene editing approaches. The second aim of the proposed studies is to identify the mouse atherosclerosis modifier gene in a genetic locus identified on chromosome 2. This aim will use sophisticated gene editing as well as a newer mouse model of atherosclerosis induced by treatment with an antisense oligonucleotide targeting the low density lipoprotein receptor. These findings may lead to novel drug targets and therapies to prevent or treat CAD. The relevance of the proposed studies is that they address a significant health concern, coronary artery disease, and will yield insight into the mechanisms that modify atherosclerosis susceptibility. The discovery of novel pathways and proteins that regulate atherosclerosis and foam cell cholesterol metabolism and inflammation offers hope for new modes of risk assessment, prevention, and therapy.