Genetic analysis of neointimal hyperplasia

新生内膜增生的遗传分析

• 批准号: 7264208
• 负责人: WEIBIN SHI
• 金额: $ 26.51万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-06 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264208
• 关键词: A Mouse; Adhesions; Angioplasty; Apolipoprotein E; Arterial Injury; Arteries; Blood; Blood Platelets; Blood Vessels; Cell Wall; Cholesterol; Clinical; Common carotid artery; Congenic Strain; Data; Deposition; Development; Diet; Endothelial Cells; Endothelium; Excision; Exposure to; Extracellular Matrix; Facility Construction Funding Category; Fasting; Fatty acid glycerol esters; Fibrin; Genetic; Genome; Growth Factor; Hybrids; Hyperlipidemia; Hyperplasia; Inbred Strains Mice; Infiltration; Inflammation; Inflammatory; Injury; Left common carotid artery structure; Lesion; Leukocytes; Link; Lipids; Lymphocyte; Matrix Metalloproteinases; Mechanics; Medial; Microsatellite Repeats; Mitogens; Monocyte Chemoattractant Proteins; Mouse Strains; Mus; Mutation; P-Selectin; Partner in relationship; Phenotype; Plasma; Polymorphic Microsatellite Marker; Proliferating; Quantitative Trait Loci; Recruitment Activity; Resistance; Site; Smooth Muscle Myocytes; Stents; Testing; Variant; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; cohort; cytokine; feeding; gene induction; genetic analysis; genome wide association study; injured; interest; light microscopy; macrophage; male; neointima formation; restenosis; success; vascular smooth muscle cell migration; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Restenosis remains the most significant clinical challenge limiting the success of angioplasty and/or stenting. Neointimal hyperplasia is the primary reason for in-stent restenosis. The objective of this proposal is to use variations among mouse strains in injury-induced neointimal hyperplasia to identify genetic factors that contribute to the development of post-angioplasty/stent restenosis. On the apolipoprotein E-deficient (apoE-/-) background, inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) differ markedly in injury-induced neointimal hyperplasia. B6.apoE-/- mice readily develop neointimal hyperplasia whereas CSH.apoE-/- mice are totally resistant to lesion formation despite the fact that the two strains have comparable hyperlipidemia on a chow diet. The F1 hybrids are intermediate in the phenotype, indicating a codominant control of the phenotype in the mice. Immediately following arterial injury is deposition of a layer of platelets at sites of vascular injury. Subsequently, leukocyte recruitment and infiltration occur. Recruited macrophages and lymphocytes and damaged endothelial cells and vascular smooth muscle cells (SMC) release cytokines, growth factors, and matrix metalloproteinases (MMP) that stimulate SMC in the medial wall to proliferate and migrate into the damaged intima. We hypothesize that genetic factors that influence the induction of cytokines and growth factors or that modulate the proliferation of vascular smooth muscle cells contribute to the variation in neointimal hyperplasia of the two strains. To test this hypothesis, B6.apoE-/- mice will be mated with CSH.apoE-/- mice to generate F1 mice, which will be subsequently intercrossed to generate a cohort of F2 mice. The male F2 mice, together with male F1 and two parental strains, will be subject to endothelial denudation of the left common carotid artery. Neointimal thickening will be quantitated by light microscopy. Blood will be collected for assessment of fasting lipid and inflammatory marker levels. Genome-wide scans will be performed using microsatellite markers to define the genetic loci that are linked to differences in the phenotypes between B6 and C3H strains. After the genome screen has detected chromosomal regions that show linkage with neointimal lesions, we will type additional closely spaced polymorphic markers to narrow the regions. One to two major QTLs for neointimal hyperplasia will be dissected through construction and analysis of congenic strains.

描述（由申请人提供）：再狭窄仍然是限制血管成形术和/或支架成功的最重要的临床挑战。新内膜增生是结内再狭窄的主要原因。该提案的目的是在损伤引起的新内膜增生中使用小鼠菌株之间的变化来确定有助于产生血管成形术/支架后再狭窄的遗传因素。在载脂蛋白E缺陷型（APOE-/ - ）背景下，近交小鼠菌株C57BL/6J（B6）和C3H/HEJ（C3H）在损伤引起的新内膜增生方面明显不同。 B6.APOE - / - 小鼠很容易发展新的增生性增生，而CSH.APOE - / - 小鼠对病变的形成完全抗性，尽管这两种菌株在食物饮食上具有可比的高脂血症。 F1杂种在表型中是中间的，表明对小鼠表型的共同控制。动脉损伤后立即是血管损伤部位的一层血小板的沉积。随后，发生白细胞募集和浸润。募集的巨噬细胞和淋巴细胞以及受损的内皮细胞以及血管平滑肌细胞（SMC）释放细胞因子，生长因子和基质金属蛋白酶（MMP），这些基质酶（MMP）刺激内侧壁中的SMC，以增殖并迁移到受损的内膜中。我们假设影响细胞因子和生长因子的诱导或调节血管平滑肌细胞的增殖的遗传因素有助于两种菌株的新内膜增生变化。为了检验该假设，B6.APOE - / - 小鼠将与CSH.APOE - / - 小鼠配对以生成F1小鼠，随后将其间断以生成一组F2小鼠。雄性F2小鼠以及雄性F1和两种亲本菌株将受到左颈动脉的内皮剥离。新膜增厚将通过光学显微镜进行定量。将收集血液以评估空腹脂质和炎症标记水平。全基因组扫描将使用微卫星标记进行定义与B6和C3H菌株之间表型差异有关的遗传基因座。在基因组筛查检测到与新内膜病变联系在一起的染色体区域之后，我们将键入额外间隔的多态性标记以缩小区域。通过构造和分析先天性菌株，将阐述用于新的增生的一到两个主要QTL。