Genetic analysis of neointimal hyperplasia

新生内膜增生的遗传分析

• 批准号: 7436143
• 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/7436143
• 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/或支架置入术成功的最重要的临床挑战。新内膜增生是支架内再狭窄的主要原因。该提案的目的是利用小鼠品系在损伤引起的内膜增生中的变异来识别导致血管成形术后/支架再狭窄发生的遗传因素。在载脂蛋白 E 缺陷 (apoE-/-) 背景下，近交小鼠品系 C57BL/6J (B6) 和 C3H/HeJ (C3H) 在损伤诱导的内膜增生方面存在显着差异。 B6.apoE-/- 小鼠很容易出现内膜增生，而 CSH.apoE-/- 小鼠则完全抵抗病变形成，尽管事实上这两种品系在食物饮食中具有相当的高脂血症。 F1 杂交体的表型处于中间状态，表明小鼠中表型的共显性控制。动脉损伤后，血管损伤部位立即沉积一层血小板。随后，发生白细胞募集和浸润。招募的巨噬细胞和淋巴细胞以及受损的内皮细胞和血管平滑肌细胞 (SMC) 释放细胞因子、生长因子和基质金属蛋白酶 (MMP)，刺激内壁中的 SMC 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诱导或调节血管平滑肌细胞增殖的遗传因素导致了两种菌株的新内膜增生的变化。为了检验这一假设，B6.apoE-/- 小鼠将与 CSH.apoE-/- 小鼠交配生成 F1 小鼠，随后将其杂交生成一组 F2 小鼠。雄性 F2 小鼠与雄性 F1 和两个亲本品系一起，将遭受左颈总动脉的内皮剥脱。新内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志物水平。将使用微卫星标记进行全基因组扫描，以确定与 B6 和 C3H 菌株之间表型差异相关的遗传位点。在基因组筛选检测到与新内膜病变相关的染色体区域后，我们将键入额外的紧密间隔的多态性标记以缩小区域。通过同源菌株的构建和分析，将剖析一到两个新内膜增生的主要 QTL。