A novel atherosclerosis locus on mouse chromosome 4

小鼠 4 号染色体上的一个新的动脉粥样硬化位点

基本信息

批准号：
8470219
负责人：
Carrie Lynn Welch
金额：
$ 37.93万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-06 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470219
关键词：
9p21 A Mouse Address Affect Alleles Aneurysm Animal Model Area Arterial Fatty Streak Atherosclerosis Biological Assay Blood CDKN2A gene Candidate Disease Gene Cell Cycle Regulation Cell Proliferation Cells Cholesterol Chromosome Mapping Chromosomes, Human, Pair 4 Clinical Pathology Collaborations Complement Complex Congenic Mice Congenic Strain Coronary Arteriosclerosis Coronary heart disease Data Developing Countries Disease Disease susceptibility Down-Regulation Etiology Evaluation Exhibits Extracellular Matrix Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Variation Genome Genotype Goals Human Human Chromosomes Human Genome Hypertension In Vitro Individual Knock-in Mouse Lesion Location Maps Measures Mediating Metabolism Modeling Mouse Strains Mus North Carolina Pathology Pathway interactions Phenotype Predisposition Proteins Quantitative Trait Loci RNA Relative (related person)Reporting Risk Risk Factors Role Series Smoking Societies Susceptibility Gene Testing Therapeutic Tissue-Specific Gene Expression Tissues Transcript Transgenic Organisms Universities Variant atherogenesis comparative congenic genetic analysis genome wide association study in vivo knockout gene macrophage meetings novel novel diagnostics public health relevance research study screening success tool versican

项目摘要

DESCRIPTION (provided by applicant): The genetics of coronary heart disease, including atherosclerosis, is poorly understood outside of traditional risk factors like blood cholesterol levels, hypertension and smoking. Although human genome-wide association studies have met with recent success in identifying candidate regions of the genome harboring disease susceptibility genes, determining genotype-phenotype relations in humans is difficult due to genetic complexity. Animal models offer an alternative approach for the genetic analysis of complex diseases. The B6-Ldlr-/- mouse strain is a widely-established model of atherosclerosis. Crossing a small region of chromosome 4 (Athsq1, Atherosclerosis susceptibility QTL1) from the wild-derived MOLF strain onto the B6-Ldlr-/- background results in ~4.5-fold increased atherosclerotic lesion area, and increased lesional accumulation of a presumably pro-atherogenic extracellular matrix component (versican), compared to B6-Ldlr-/- controls. The location of the causative gene within the MOLF-derived interval has been narrowed to a region that includes ~130 genes. Interestingly, this region contains the mouse homology with a widely-replicated human locus for CHD and aneurysm. The major goals of this proposal are: I) identify the gene(s) underlying the murine Athsq1 locus; 2) to determine the relevance of Athsq1 to the human chr 9p21 CHD locus; and 3) to determine the mechanism by which the underlying gene may influence versican accumulation in lesions and accelerated atherogenesis. A standard mouse genetics approach will be utilized to narrow the location of the underlying gene. In addition, differential gene expression in relevant tissues will be determined to predict candidate genes within the interval. Mechanistic studies in primary cells derived from Athsq1 and B6-Ldlr-/- controls will be performed to assess the role of candidate genes in versican accumulation and potential pro-atherogenic pathways, in vitro. These studies will include gene-specific knockdowns. Proof of causality will be addressed with atherosclerosis studies, in vivo, using transgenic, gene knockout or gene knock-in mice. Finally, atherosclerotic vessels from individuals carrying risk or non-risk alleles at the 9p21 CHD locus will be assessed for relative accumulation of versican. The long range goals of this proposal are to identify a novel gene(s) underlying susceptibility to atherosclerosis, potentially suggesting new diagnostic and/or therapeutic strategies for CHD.

描述（由申请人提供）：除了血液胆固醇水平、高血压和吸烟等传统危险因素之外，人们对冠心病（包括动脉粥样硬化）的遗传学知之甚少。尽管人类全基因组关联研究最近在识别含有疾病易感基因的基因组候选区域方面取得了成功，但由于遗传复杂性，确定人类基因型-表型关系很困难。动物模型为复杂疾病的遗传分析提供了另一种方法。 B6-Ldlr-/- 小鼠品系是广泛建立的动脉粥样硬化模型。将野生来源的 MOLF 菌株的 4 号染色体小区域（Athsq1，动脉粥样硬化易感性 QTL1）交叉到 B6-Ldlr-/- 背景上，导致动脉粥样硬化病变面积增加约 4.5 倍，并增加可能亲-的病变积累。与 B6-Ldlr-/- 对照相比，致动脉粥样硬化细胞外基质成分 (versican)。 MOLF 衍生区间内致病基因的位置已缩小到包含约 130 个基因的区域。有趣的是，该区域与广泛复制的人类冠心病和动脉瘤基因座具有小鼠同源性。该提案的主要目标是： I) 鉴定小鼠 Athsq1 位点的基因； 2) 确定Athsq1与人类chr 9p21 CHD位点的相关性； 3) 确定潜在基因可能影响病变中多功能蛋白聚糖积累并加速动脉粥样硬化形成的机制。将利用标准小鼠遗传学方法来缩小潜在基因的位置。此外，还将确定相关组织中的差异基因表达，以预测该区间内的候选基因。将在源自 Athsq1 和 B6-Ldlr-/- 对照的原代细胞中进行机制研究，以评估候选基因在体外多功能蛋白聚糖积累和潜在促动脉粥样硬化途径中的作用。这些研究将包括基因特异性敲低。将使用转基因、基因敲除或基因敲入小鼠通过体内动脉粥样硬化研究来证明因果关系。最后，将评估 9p21 CHD 基因座携带风险或非风险等位基因的个体的动脉粥样硬化血管的多功能蛋白聚糖的相对积累。该提案的长期目标是确定潜在的动脉粥样硬化易感性新基因，可能为冠心病提出新的诊断和/或治疗策略。