Id3 and VSMC in Murine and Human Atherosclerosis

Id3 和 VSMC 在小鼠和人类动脉粥样硬化中的作用

• 批准号: 10004164
• 负责人: Coleen A McNamara
• 金额: $ 67.1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-28 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004164
• 关键词: Alanine; Alleles; Amino Acids; Animals; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Automobile Driving; Binding; Biology; Blood Vessels; CRISPR/Cas technology; Cause of Death; Cell Adhesion Molecules; Cell Count; Cell Lineage; Cell physiology; Cells; Cellular biology; Characteristics; Collaborations; Coronary Stenosis; Coronary artery; Cytometry; Data; Deposition; Development; Diabetes Mellitus; Disease; Gene Expression; Gene Mutation; Genes; Genetic Engineering; Genetic Polymorphism; Genetic Risk; Genomics; Growth; Heart; Heritability; Histology; Human; Image; Image Analysis; Immune; Inflammation; Inflammation Mediators; Inflammatory; Iowa; Knock-out; Lead; Lesion; Link; Measures; Medial; Mediating; Minor; Modeling; Molecular; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Multivariate Analysis; Mus; Necrosis; Null Lymphocytes; Participant; Phenotype; Pluripotent Stem Cells; Pre-Clinical Model; Prevention; Process; Proteomics; Reproducibility; Research Design; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Series; Single Nucleotide Polymorphism; Smooth Muscle Myocytes; Stimulus; System; Techniques; Testing; Thick; Threonine; Translating; Tumor-infiltrating immune cells; Ultrasonography; Universities; Variant; Vascular Cell Adhesion Molecule-1; Vascular Smooth Muscle; calcification; cell growth; cohort; coronary artery calcium; coronary plaque; dimer; genome editing; human subject; indexing; machine learning algorithm; macrophage; mortality; mouse model; new therapeutic target; novel; oxidized low density lipoprotein; promoter; risk variant; transcriptome sequencing; vascular smooth muscle cell proliferation; virtual

Despite major advances in prevention and treatment of atherosclerotic cardiovascular disease (ASCVD), it remains a major cause of deaths worldwide. As ASCVD is a heritable and polygenic disorder, identification of ASCVD-associated single nucleotide polymorphisms (SNP) in humans and elucidation of their effect on ASCVD biology is needed to fully understand and impact on this unmet residual risk. One such human polymorphism in the ID3 gene (rs11574) was associated with ASCVD in 3 distinct human cohorts. Notably, this SNP significantly attenuates ID3 function and studies in pre-clinical models confirm a critical role for ID3 in atheroprotection. We have previously shown that loss of ID3 inhibits vascular smooth muscle cell (VSMC) proliferation and promotes VSMC expression of inflammatory factors, processes linked to increase atherosclerosis. In collaboration with Dr. Gary Owens, we have generated a mouse model with VSMC lineage tracing and VSMC-specific deletion of ID3 to study ID3-dependent VSMC specific changes during the course of lesion development in the context of the whole animal. We have developed a comprehensive CyTOF panel to identify and quantitate key cellular and intracellular changes in VSMC and other lesional cells in the aorta during the course of atherosclerosis development in these mice. To translate murine findings to humans, we have utilized CRISPR/Cas9 genetic engineering to knock out ID3 and produce the full allelic series of rs11574 in human cells and validated a reproducible system for differentiation of human inducible pluripotent stem cells (iPSCs) to VSMC. We will quantify the changes in VSMC phenotype in iPSC-derived VSMC with the full allelic series of rs11574. To further translate murine findings to humans, intravascular ultrasound virtual histology (IVUS-VH) will be measured in human coronary arteries and analyzed with cutting edge image analysis techniques in collaboration with Dr. Milan Sonka at the University of Iowa. As such, our group is uniquely poised to dissect the role of this ASCVD-associated SNP and translate findings to humans. We hypothesize: that loss of ID3 in VSMCs will inhibit VSMC growth and promote a phenotype that exacerbates vessel wall inflammation and atherosclerosis lesion development; that human ID3 encoded by the risk allele aggravates these atherogenic VSMC functions; and that human subjects with the risk allele have larger coronary plaques with increased fatty deposits, necrotic cores and calcification compared to subjects homozygous for the common allele.

尽管在预防和治疗动脉粥样硬化性心血管疾病（ASCVD）方面取得了重大进展，但它仍然存在