Genetic Predisposition for Intimal Hyperplasia in Mice

小鼠内膜增生的遗传倾向

• 批准号: 7983436
• 负责人: RENEE C LEBOEUF
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983436
• 关键词: Affect; Angioplasty; Arteries; Biological Markers; Blood Vessels; Blood flow; Caliber; Candidate Disease Gene; Carotid Arteries; Carotid Artery Injuries; Characteristics; Clinical; Collection; Cultured Cells; DNA Sequence; Data; Data Linkages; Deposition; Development; Endarterectomy; Exhibits; Extracellular Matrix; FVB Mouse; Family; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Genetically Engineered Mouse; Genotype; Goals; Growth; Haplotypes; Health; Human; Human Genetics; Hyperplasia; Inbred Strain; Inbred Strains Mice; Individual; Injury; Lesion; Ligation; Ligature; Mediating; Mediator of activation protein; Molecular; Mouse Strains; Mus; Myocardial Infarction; Pathology; Pathway interactions; Phenotype; Population; Positioning Attribute; Predisposition; Process; Quantitative Trait Loci; Research; Resistance; Risk; Smooth Muscle Myocytes; Stroke; System; Testing; Thrombosis; Validation; Veins; Work; cell type; cohort; genetic linkage; genome wide association study; human SSPN protein; interest; migration; novel; public health relevance; reconstruction; resistant strain; response; response to injury; strain injury; therapy development

DESCRIPTION (provided by applicant): Smooth muscle cell (SMC) accumulation and extracellular matrix deposition in the intima are major characteristics of neointimal hyperplasia (IH) which occurs frequently following all forms of vascular reconstruction, including stenting, angioplasty, endarterectomy and vein grafts. A common result of IH is the reduction of the vessel lumen diameter leading to important clinical problems such as angina, stroke, thrombosis and myocardial infarction. It is our goal to identify biomarkers to assess risk of developing IH and molecular mediators for the development of therapies to treat susceptible vessels. Among mouse strains, there is a wide range of responses to carotid artery injury as induced by ligature, slow flow or endothelial denudation ranging from mice that are completely resistant those which develop large neointimal lesions. Here, we exploit these phenotypic differences by using genetic linkage and association studies to identify genes modulating vascular pathology in carotid arteries. Since the last submission, we have altered the emphasis of our outstanding research team to include family linkage and association study expertise. We also nearly doubled an F2 population between FVB (susceptible) and C57BL/6 (resistant) strains and identified 6 quantitative trait loci (QTL). An identity by descent analysis was performed across 10 inbred strains to reduce QTL intervals which yielded 8 candidate genes worthy of further study. We also screened 9 inbred mouse strains in anticipation of entering them into a large association study. We present validation data for one candidate gene and show its relevance to the IH process. Overall, we expect to use this unbiased system for the discovery of novel genes controlling IH. Work will be conducted as described in three Specific Aims: (1) Identify chromosomal intervals containing genes modulating susceptibility and resistance to injury-induced neointimal hyperplasia (IH). We will use classic linkage studies to identify QTL and haplotype analysis across F2 mice to eliminate regions that are shared identical by descent. (2) Identify genes and molecular pathways mediating responsiveness to carotid artery injury using genome wide association studies. We will use a mouse diversity panel of ~100 inbred strains for which genotypes are already known and obtain IH phenotypes for association studies. (3) Validate and determine functions for potential candidate genes controlling IH. Candidate genes discovered in Aims 1 and 2 will be studied further here. Such studies will include identification of cell type(s) involved in expression, characterization of molecular functions in cultured cells, and development of appropriate genetically engineered mice. Overall, the strengths of this proposal include: (a) the novelty of the topic; (b) outstanding research team; (c) currently existing QTL for IH; and (d) strong preliminary data identifying a candidate gene with potential IH-modulating activity which demonstrates the utility of our approach. Further, the health topic is of high significance as tens of thousands of individuals are affected by vascular injury each year. PUBLIC HEALTH RELEVANCE: Smooth muscle cell (SMC) accumulation and extracellular matrix deposition in the intima are major characteristics of neointimal hyperplasia (IH) which occurs frequently following all forms of vascular reconstruction, including stenting, angioplasty, endarterectomy and vein grafts. It is our goal to identify biomarkers to assess risk of developing IH and molecular mediators for the development of therapies to treat susceptible vessels. This will be done using genetic approaches.

描述（由申请方提供）：内膜中平滑肌细胞（SMC）积聚和细胞外基质沉积是新生内膜增生（IH）的主要特征，其在所有形式的血管重建（包括支架植入术、血管成形术、动脉内膜切除术和静脉移植物）后经常发生。IH的常见结果是血管腔直径减小，导致重要的临床问题，如心绞痛、中风、血栓形成和心肌梗死。我们的目标是确定生物标志物，以评估发展IH的风险和分子介质，以开发治疗易感血管的疗法。 在小鼠品系中，对由结扎、慢血流或内皮剥脱诱导的颈动脉损伤有广泛的反应，范围从完全耐受的小鼠到发展大的新生内膜病变的小鼠。在这里，我们利用这些表型差异，通过遗传连锁和关联研究，以确定基因调节颈动脉血管病变。 自上次提交以来，我们已经改变了我们优秀的研究团队的重点，包括家庭联系和协会研究的专业知识。我们还将FVB（感病）和C57 BL/6（抗病）品系之间的F2群体几乎加倍，并鉴定了6个数量性状位点（QTL）。对10个自交系进行了同源性分析，以减少QTL间隔，得到8个值得进一步研究的候选基因。我们还筛选了9个近交系小鼠品系，期望将其纳入大型关联研究。我们提出了一个候选基因的验证数据，并显示其相关性的IH过程。总的来说，我们希望使用这个公正的系统发现新的基因控制IH。 工作将按照三个特定目标中所述进行：（1）鉴定含有调节损伤诱导的新生内膜增生（IH）易感性和抗性的基因的染色体间隔。我们将使用经典的连锁研究，以确定QTL和F2小鼠的单倍型分析，以消除区域共享相同的血统。(2)利用全基因组关联研究鉴定介导颈动脉损伤反应的基因和分子通路。我们将使用一个小鼠多样性面板的基因型已经知道，并获得IH表型的关联研究约100近交系。(3)筛选并确定控制IH的潜在候选基因的功能。在目标1和2中发现的候选基因将在这里进一步研究。这些研究将包括鉴定参与表达的细胞类型、表征培养细胞中的分子功能以及开发适当的基因工程小鼠。总的来说，这个建议的优势包括：（a）这个主题的新奇;（B）优秀的研究团队;（c）目前现有的IH QTL;和（d）强有力的初步数据，确定了一个候选基因与潜在的IH调节活性，这表明我们的方法的实用性。此外，健康主题具有高度意义，因为每年有数万人受到血管损伤的影响。 公共卫生关系：内膜中平滑肌细胞（SMC）积聚和细胞外基质沉积是新生内膜增生（IH）的主要特征，其经常发生在所有形式的血管重建（包括支架植入术、血管成形术、动脉内膜切除术和静脉移植物）之后。我们的目标是确定生物标志物，以评估发展IH的风险和分子介质，以开发治疗易感血管的疗法。这将使用遗传方法来完成。