Genetic Predisposition for Intimal Hyperplasia in Mice

小鼠内膜增生的遗传倾向

• 批准号: 8111887
• 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/8111887
• 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 association; genetic linkage; genome wide association study; human SSPN protein; interest; migration; novel; public health relevance; reconstruction; resistant strain; response; response to 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（由申请人提供）：内膜中的平滑肌细胞（SMC）积累和细胞外基质沉积是新内膜增生（IH）的主要特征，它经常遵循所有形式的血管重建形式，包括支架，血管成形术，血管成形术，末端切除术和静脉移植。 IH的常见结果是减少血管管腔直径，导致重要的临床问题，例如心绞痛，中风，血栓形成和心肌梗塞。我们的目标是确定生物标志物评估开发IH和分子介质的风险，以开发治疗易感血管的疗法。 在小鼠菌株中，由于韧带，缓慢的流动或内皮剥离引起的颈动脉损伤的反应广泛，这些小鼠完全抵抗那些出现大型新内膜病变的小鼠。在这里，我们通过使用遗传联系和关联研究来利用这些表型差异来鉴定调节颈动脉血管病理学的基因。 自上次提交以来，我们改变了杰出的研究团队的重点，包括家庭联系和协会研究专业知识。我们在FVB（易感）和C57BL/6（抗性）菌株之间的F2人群也几乎翻了一番，并确定了6个定量性状基因座（QTL）。在10个近交菌株中进行了下降分析的身份，以减少QTL间隔，从而产生了8种值得进一步研究的候选基因。我们还筛选了9种近交小鼠菌株，以期进入大型关联研究。我们提供了一个候选基因的验证数据，并显示其与IH过程的相关性。总体而言，我们希望将这种无偏的系统用于发现控制IH的新基因。 工作将如三个特定目的所述进行：（1）确定染色体间隔，其中包含调节易感性和对损伤引起的新内膜增生（IH）的抗性的基因。我们将使用经典的链接研究来识别F2小鼠的QTL和单倍型分析，以消除通过下降共享相同的区域。 （2）确定使用基因组广泛关联研究介导对颈动脉损伤的反应性的基因和分子途径。我们将使用一个〜100个近交菌株的小鼠多样性面板，为其基因型已经知道并获得IH表型进行关联研究。 （3）验证并确定控制IH的潜在候选基因的功能。 AIMS 1和2中发现的候选基因将在这里进一步研究。此类研究将包括鉴定涉及表达的细胞类型，培养细胞中分子功能的表征以及开发适当的基因工程小鼠。总体而言，该提议的优势包括：（a）该主题的新颖性； （b）出色的研究团队； （c）当前为IH现有的QTL； （d）强大的初步数据，识别具有潜在IH调节活性的候选基因，这证明了我们方法的实用性。此外，健康主题具有很高的意义，因为每年成千上万的人受到血管损伤的影响。 公共卫生相关性：内膜中的平滑肌细胞（SMC）积累和细胞外基质沉积是新内膜增生（IH）的主要特征，它经常遵循各种形式的血管重建，包括支架，血管成形术，内部骨膜内切除术和静脉移植。我们的目标是确定生物标志物评估开发IH和分子介质的风险，以开发治疗易感血管的疗法。这将使用遗传方法完成。