Role for S1P2 in the Arterial Injury Response

S1P2 在动脉损伤反应中的作用

• 批准号: 7522560
• 负责人: GUENTER DAUM
• 金额: $ 41.5万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522560
• 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; Purpose; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：内膜增生是由内膜平滑肌细胞（SMC）的增殖和迁移引起的，并导致动脉重建后的再狭窄（血管的重新闭塞）。该提案研究了内膜生长发生的可能性，因为通常抑制损伤后 SMC 过度增殖的途径受到抑制。我们发现，缺乏 1-磷酸鞘氨醇 (S1P2) 2 型受体（但野生型对应物则不然）的小鼠的颈动脉损伤会导致大的新内膜的形成。由于 S1P2 缺陷小鼠发育正常并且不表现出任何血管表型，因此 S1P2 显然在脉管系统的发育中不发挥关键作用。我们的总体假设是 S1P 在损伤后产生并与 S1P2 结合，从而导致血清反应因子及其心肌素样蛋白家族的辅助因子激活。已知该转录因子复合物可调节 SMC 特异性基因的表达，我们假设这些基因抑制 SMC 增殖。 S1P2 敲除小鼠中不存在这种抑制途径，这可能是这些动物因动脉损伤而出现大面积内膜病变的原因。该提案的目标是检验这一假设，并提出了四个具体目标。在目标 1 中，我们将测量野生型和 S1P 缺陷小鼠受损动脉中 SMC 特异性基因的表达。在目标 2 中，我们将定义 SMC 中表达的所有三种 S1P 受体在 SRF 依赖性基因调节中的作用。在目标 3 中，我们将表征由 S1P2 激活并调节 SMC 特异性基因表达的转录复合物。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，这些基因在损伤反应中受 S1P2 直接控制。公众健康相关性：再狭窄是动脉修复的一种严重且昂贵的并发症，发生时间约为 10 年。 30%的患者。 S1P2 表达水平和信号传导的变化可能决定内膜病变是否发生。因此，S1P2 途径中的蛋白质可能构成内膜生长药理学控制的有希望的新靶标。