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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

基本信息

批准号：
10306932
负责人：
Jonathan D Smith
金额：
$ 63.26万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
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/10306932
关键词：
3&apos Untranslated Regions Address 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 Inflammasome Inflammation Interleukin-1 Knowledge Lead Lesion Leukotriene B4 Lipids Low Density Lipoprotein Receptor Lysosomes Manuscripts Mediating Messenger RNA Metabolism Methods Molecular Morbidity - disease rate Mouse Strains Mus Names Obesity Pathway interactions Pattern Pharmaceutical Preparations Phenotype Play Predisposition Preparation Prevention Prevention therapy Program Research Project Grants Proteins Publishing Quantitative Trait Loci Quick Test for Liver Function RNA Splicing Recombinants Resistance Resolution Risk Risk Assessment Risk Factors Role 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 in vitro Model in vitro activity in vivo innovation insight interest macrophage 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 targeted treatment trait transcriptomics

项目摘要

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。