Role for S1P2 in the Arterial Injury Response

S1P2 在动脉损伤反应中的作用

• 批准号: 8300956
• 负责人: RENEE C LEBOEUF
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300956
• 关键词: Animals; Arterial Injury; Arteries; Binding; Biological Assay; Blood Vessels; Carotid Arteries; Cell Differentiation process; Cell Proliferation; Chemotactic Factors; Complex; Complication; Data Set; Detection; Development; ERG gene; Enhancers; Event; Exhibits; Gene Expression; Genes; Goals; Growth; Hyperplasia; Individual; Injury; Introns; Kinetics; Knockout Mice; Lesion; Ligation; Measures; Messenger RNA; Microarray Analysis; Mitogens; Mus; Null Lymphocytes; Pathway interactions; Patients; Phenotype; Play; Principal Investigator; Process; Protein Family; Proteins; Public Health; Regulation; Regulatory Pathway; Role; Serum Response Factor; Signal Transduction; Small Interfering RNA; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Sphingosine-1-Phosphate Receptor; Technology; Testing; Time; Variant; Wild Type Mouse; calponin; cofactor; injured; migration; myocardin; novel; programs; reconstruction; repaired; response; response to injury; restenosis; rho; transcription factor

Project Summary: Intimal hyperplasia is caused by proliferation and migration of intimal smooth muscle cells (SMCs) and contributes to restenosis (the re-occlusion of vessels) after arterial reconstruction. This proposal investigates the possibility that intimal growth occurs because a pathway that normally inhibits excessive proliferation of SMCs after injury is suppressed. We have found that carotid injury in a mouse lacking the type-2 receptor for sphingosine-1-phosphate (S1P2), but not in their wild-type counterpart, results in the formation of a large neointima. Because S1P2-deficient mice develop normally and do not exhibit any vascular phenotype, S1P2 does apparently not play a critical role in the development of the vasculature. Our overall hypothesis is that S1P is generated after injury and binds to S1P2, which causes activation of serum-response factor and its cofactor of the myocardin-like protein family. This transcription factor complex is known to regulate expression of SMC-specific genes, and we hypothesize that these genes inhibit SMC proliferation. This inhibitory pathway is absent in the S1P2 knock-out mouse, and this might be the reason that these animals develop large intimal lesions in response to arterial injury. The goal of this proposal is to test this hypothesis, and four specific aims are proposed. In aim 1, we will measure expression of SMC- specific genes in injured arteries of wild-type and S1P-deficient mice. In aim 2, we will define a role for all three S1P receptors expressed in SMCs in the regulation of SRF- dependent genes. In aim 3, we will characterize the transcriptional complex that is activated by S1P2 and regulates the expression of SMC-specific genes. In aim 4, we will use micro array technology to identify novel genes in the vessel wall that are directly controlled by S1P2 in response to injury. Relevance to public health: Restenosis is a serious and costly complication of arterial repair which occurs in ca. 30% of patients. Variations in S1P2 expression levels and signaling might determine if intimal lesions develop. Thus, proteins in the S1P2 pathway may constitute promising novel targets to pharmacological control of intimal growth. Relevance to public health: Restenosis is a serious and costly complication of arterial repair which occurs in ca. 30% of patients. Variations in S1P2 expression levels and signaling might determine if intimal lesions develop. Thus, proteins in the S1P2 pathway may constitute promising novel targets to pharmacological control of intimal growth.

项目概要：内膜增生是由于内膜增生、迁移而引起的。 平滑肌细胞 (SMC) 并导致再狭窄（血管重新闭塞） 动脉重建后。该提案调查了内膜生长的可能性 发生的原因是通常抑制 SMC 过度增殖的途径 伤害被抑制。我们发现缺乏 2 型的小鼠颈动脉损伤 1-磷酸鞘氨醇 (S1P2) 受体，但野生型对应物中没有， 导致大的新内膜的形成。因为 S1P2 缺陷小鼠发育 通常情况下，不表现出任何血管表型，S1P2 显然不发挥作用 在脉管系统的发育中起关键作用。我们的总体假设是 S1P 损伤后产生并与 S1P2 结合，导致血清反应激活 心肌素样蛋白家族的因子及其辅助因子。该转录因子 已知复合物可调节 SMC 特异性基因的表达，我们假设 这些基因抑制 SMC 增殖。 S1P2 中不存在该抑制途径 基因敲除小鼠，这可能是这些动物发育出大内膜的原因 动脉损伤引起的病变。该提案的目的是检验这个假设， 并提出了四项具体目标。在目标 1 中，我们将测量 SMC-的表达 野生型和 S1P 缺陷小鼠受损动脉中的特定基因。在目标 2 中，我们将 定义了 SMC 中表达的所有三种 S1P 受体在 SRF 调节中的作用 依赖基因。在目标 3 中，我们将表征转录复合物，即 由 S1P2 激活并调节 SMC 特异性基因的表达。在目标 4 中，我们 将使用微阵列技术来识别血管壁中的新基因，这些基因直接 由 S1P2 控制以响应损伤。 与公共卫生的相关性：再狭窄是一种严重且昂贵的动脉并发症 修复发生在大约。 30%的患者。 S1P2表达水平的变化 信号传导可能决定内膜病变是否发生。因此，S1P2 通路中的蛋白质 可能成为药物控制内膜生长的有希望的新靶点。与公共卫生的相关性：再狭窄是动脉修复的一种严重且昂贵的并发症， 发生在大约。 30%的患者。 S1P2 表达水平和信号传导的变化可能决定是否 内膜病变发展。因此，S1P2 通路中的蛋白质可能构成有希望的新靶点 内膜生长的药物控制。

项目成果

Sphingosine-1-phosphate receptor 3 promotes neointimal hyperplasia in mouse iliac-femoral arteries.

• DOI: 10.1161/atvbaha.111.241034
• 发表时间: 2012-04
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Shimizu T;De Wispelaere A;Winkler M;D'Souza T;Caylor J;Chen L;Dastvan F;Deou J;Cho A;Larena-Avellaneda A;Reidy M;Daum G
• 通讯作者: Daum G