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.

项目概述：内膜增生是由内膜的增殖和迁移引起的， 平滑肌细胞（SMC），并有助于再狭窄（血管再闭塞） 动脉重建后这项提议调查了内膜生长的可能性， 发生是因为一种通常抑制SMC过度增殖的途径， 伤害被抑制了。我们发现，缺乏2型糖尿病的小鼠颈动脉损伤， 鞘氨醇-1-磷酸（S1 P2）的受体，但在其野生型对应物中没有， 导致形成大的新生内膜。因为S1 P2缺陷的小鼠 正常情况下，S1 P2不表现出任何血管表型，显然不发挥作用。 在脉管系统的发育中起着关键作用。我们的总体假设是，S1 P是 损伤后产生，并结合S1 P2，引起血清反应的激活 因子及其辅因子的myocardin样蛋白家族。该转录因子 已知复合物调节SMC特异性基因的表达，我们假设 这些基因抑制SMC增殖。这种抑制途径在S1 P2中不存在。 敲除小鼠，这可能是这些动物发展大内膜的原因 对动脉损伤的反应。本提案的目的是检验这一假设， 并提出了四个具体目标。在目的1中，我们将测量SMC的表达- 野生型和S1 P缺陷小鼠受损动脉中的特异性基因。在目标2中，我们 确定SMC中表达的所有三种S1 P受体在SRF调节中的作用- 依赖基因在目标3中，我们将描述转录复合物的特征， 由S1 P2激活并调节SMC特异性基因的表达。在目标4中， 将使用微阵列技术来识别血管壁中的新基因， 由S1 P2控制，以响应损伤。 与公共卫生的相关性：呼吸暂停是一种严重和昂贵的动脉并发症， 修复发生在CA。30%的患者。S1 P2表达水平的变化和 信号传导可能决定内膜损伤是否发展。因此，S1 P2通路中的蛋白质 可能构成有前途的新靶点，以药理学控制内膜生长。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CA。30%的患者。S1 P2表达水平和信号传导的变化可能决定是否 内膜损伤发展。因此，S1 P2通路中的蛋白质可能构成有希望的新靶点， 药物控制内膜生长。

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