Genetic modifiers of atherosclerosis and macrophage phenotypes

动脉粥样硬化和巨噬细胞表型的遗传修饰

• 批准号: 10626053
• 负责人: Jonathan D Smith
• 金额: $ 61.88万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626053
• 关键词: 3' Untranslated Regions; Affect; Alleles; Antisense Oligonucleotides; Apolipoprotein E; Area; Atherosclerosis; Autophagocytosis; Bioinformatics; Bone Marrow; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular Diseases; Cell Culture Techniques; Cessation of life; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Chromosome 2; Chromosomes; Congenic Mice; Coronary Arteriosclerosis; DBA/2 Mouse; Data; Development; Diagnosis; Endothelial Cells; Exons; Foam Cells; Foundations; Gene Modified; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Heart Diseases; Heritability; Human; Human Genome; In Vitro; Incidence; Incubated; Inflammasome; Inflammation; Knowledge; Lesion; Leukotriene B4; Lipids; Low Density Lipoprotein Receptor; Lysosomes; Macrophage; Manuscripts; Maps; Mediating; Messenger RNA; Metabolism; Methods; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Names; Obesity; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Predisposition; Preparation; Prevention; Program Research Project Grants; Proteins; Publishing; Quantitative Trait Loci; RNA Splicing; Recombinants; Resistance; Resolution; Risk; Risk Assessment; Risk Factors; Testing; Tissues; United States; Validation; Variant; Woman; Work; acetyl-LDL; causal variant; cell type; density; embryonic stem cell; gene discovery; genetic approach; genetic variant; genome wide association study; genomic locus; improved; in vitro Model; in vitro activity; in vivo; innovation; insight; interest; men; mortality; mouse genetics; mouse model; new therapeutic target; novel; novel diagnostics; novel therapeutics; prevent; public health relevance; single-cell RNA sequencing; sterol O-acyltransferase 1; trait; transcriptomics

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.

摘要 心脏病是美国男性和女性的头号杀手。尽管 心血管疾病死亡的发生率下降了，它仍然占到每3人中就有1人死亡 死亡。动脉粥样硬化导致的冠状动脉疾病(CAD)是导致这些疾病的主要原因 死亡。尽管对冠心病危险因素和治疗药物的有效性的了解有所增加 其中，CAD问题并没有得到解决。大型人类基因组全关联研究 已经发现了许多与CAD相关的常见遗传变异，但只有一小部分 可遗传的风险已经被发现了。这项建议旨在进行小鼠遗传和 鉴定巨噬细胞动脉粥样硬化修饰基因和遗传修饰基因的基因组研究 泡沫细胞脂滴新陈代谢和炎症，深入了解 规范这些途径。拟议研究的第一个目标是确定 导致体外巨噬细胞表型的相关基因和遗传变异 先进的遗传和基因编辑方法。拟议研究的第二个目标是 在染色体上确定一个遗传位点上的小鼠动脉粥样硬化修饰基因 2.这个目标将使用复杂的基因编辑以及较新的小鼠模型 低密度靶向反义寡核苷酸治疗动脉粥样硬化 脂蛋白受体。这些发现可能导致新的药物靶点和治疗方法来预防或 对待CAD。拟议的研究的相关性在于，它们解决了一个重要的健康问题 关注，冠状动脉疾病，并将深入了解改变 动脉粥样硬化易感性。新的调控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为新的 风险评估、预防和治疗的模式。

项目成果

Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice.

• DOI: 10.1016/j.isci.2023.106076
• 发表时间: 2023-02-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Traughber, Alicia;Deshpande, Gauravi M.;Neupane, Kalash;Bhandari, Nilam;Khan, Mariam R.;McMullen, Megan R.;Swaidani, Shadi;Opoku, Emmanuel;Muppala, Santoshi;Smith, Jonathan D.;Nagy, Laura E.;Gulshan, Kailash
• 通讯作者: Gulshan, Kailash

Impavido attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice.

Impavido 可减轻高脂血症小鼠的炎症、减少动脉粥样硬化并改变肠道微生物群。

• DOI: 10.1016/j.isci.2023.106453
• 发表时间: 2023
• 期刊: iScience
• 影响因子: 5.8
• 作者: Traughber,CAlicia;Iacano,AmandaJ;Neupane,Kalash;Khan,MariamR;Opoku,Emmanuel;Nunn,Tina;Prince,Ashutosh;Sangwan,Naseer;Hazen,StanleyL;Smith,JonathanD;Gulshan,Kailash
• 通讯作者: Gulshan,Kailash