Sphingolipid Signaling in Endothelial Function

内皮功能中的鞘脂信号转导

• 批准号: 8247022
• 负责人: MENQ-JER LEE
• 金额: $ 33.74万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247022
• 关键词: Actins; Adherens Junction; Animal Model; Architecture; Area; Binding; Biological; Biological Models; Blood Vessels; Cell Nucleus; Cell membrane; Chemotaxis; Complex; Coupled; Cytoskeleton; Electrical Resistance; Elements; Endothelial Cells; Equilibrium; Event; Extracellular Matrix; Extravasation; Family; Focal Adhesion Kinase 1; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Silencing; Genetic Transcription; Goals; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Histamine; Homeostasis; Importins; In Vitro; Integrins; Investigation; Lead; Ligation; Lipids; Mediating; Microfilaments; Modeling; Molecular; Mutate; Nuclear; Nuclear Translocation; Pathway interactions; Permeability; Physiological; Play; RNA; Rattus; Regulation; Research; Role; Running; Serum; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Sprague-Dawley Rats; Talin; Technology; Testing; Therapeutic; Tight Junctions; Transcriptional Activation; Translating; Vascular Endothelial Cell; angiogenesis; cadherin 5; connective tissue growth factor; human EMS1 protein; in vivo; in vivo Model; mutant; novel; nucleocytoplasmic transport; receptor; receptor-mediated signaling; response; rho; sphingosine 1-phosphate; success

Sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, regulates various biological activities of vasculature. Most, if not all, S1P functions are mediated by the S1P family of G-protein-coupled receptors (GPCRs). Five S1P receptor subtypes (S1P1-S1P5) have been identified. Previously, we showed that S1P1, a Gi-coupled GPCR, regulates endothelial cytoskeletal architectures, chemotaxis, formation of adherens junctions (AJs) and tight junctions (TJs), as well as morphogenic and angiogenic responses. The S1P/ S1P1 signaling enhances the transendothelial electrical resistance (TEER), an indicator of vascular barrier integrity. Moreover, the S1P1-transduced signaling inhibits the histamine-induced vessel leakage in the Sprague Dawley (SD) rat. Mechanistically, S1P stimulation results in the formation of two distinct Zonula Occludens-1 (ZO-1) complexes which regulate the TJ formation and chemotactic response in endothelial cells (ECs). These results suggest that S1P signaling via the S1P1 receptor is important in the regulation of vascular functions. Importantly, we recently observed that S1P1 receptor is present in the nuclear compartment of ECs. Furthermore, we demonstrate that importin ¿1 directly interacts with the third intracellular loop (i3) of S1P1 receptor and the nuclear translocation of S1P1 receptor is mediated by the importin ¿1-Ran nuclear transport machinery. Inhibition of nuclear translocation of S1P1 has no effect on the initial S1P-mediated TEER rise, yet markedly diminishes its sustained rise. Furthermore, endothelial nuclear S1P-S1P1 signaling axis stimulates the transcription of Cyr61 and CTGF, two growth factors which are functionally important in angiogenesis. Together, these results suggest the central hypothesis of this proposal: "both the plasma membrane (PM-) and nuclear (N)-S1P1 receptors play critical roles in regulating endothelial functions, particularly in vascular integrity and angiogenesis". The main goal of this proposal is to characterize the respective signaling cascades and biological responses mediated by the PM- and N-S1P1 receptors with particular focus on the regulation of vessel integrity function and angiogenic response. Three specific aims are planned in this proposal, and they are: (1) characterize the mechanisms of S1P1 receptor-mediated endothelial barrier integrity function, (2) determine the functions of nuclear S1P1 receptor in ECs, and (3) utilizing animal models to elucidate the physiological functions of S1P1 receptor in vivo. The success of this proposed research will not only lead to the discovery of novel mechanisms mediating GPCR signaling, but may also develop into future therapeutic usages.

鞘氨醇-1-磷酸（S1P）是一种经血清传播的生物活性脂质，可调节动物的多种生物活性

项目成果

Proteomic and functional characterisation of platelet microparticle size classes.

• DOI: 10.1160/th09-04-243
• 发表时间: 2009-10
• 期刊: Thrombosis and haemostasis
• 影响因子: 6.7
• 作者: Dean WL;Lee MJ;Cummins TD;Schultz DJ;Powell DW
• 通讯作者: Powell DW

To stay or to leave: Stem cells and progenitor cells navigating the S1P gradient.

• DOI: 10.4331/wjbc.v2.i1.1
• 发表时间: 2011-01-26
• 期刊: World journal of biological chemistry
• 作者: Liu J;Hsu A;Lee JF;Cramer DE;Lee MJ
• 通讯作者: Lee MJ

Ligand-induced nuclear translocation of S1P(1) receptors mediates Cyr61 and CTGF transcription in endothelial cells.

• DOI: 10.1007/s00418-008-0521-9
• 发表时间: 2009-02
• 期刊: HISTOCHEMISTRY AND CELL BIOLOGY
• 影响因子: 2.3
• 作者: Estrada, Rosendo;Wang, Lichun;Jala, Venkatakrishna R.;Lee, Jen-Fu;Lin, Cheng-Yon;Gray, Robert D.;Haribabu, Bodduluri;Lee, Menq-Jer
• 通讯作者: Lee, Menq-Jer