CXC chemokine receptors, angiogenesis and angiostasis

血管生成在发育和妊娠、伤口愈合、缺血组织血运重建和肿瘤发生过程中至关重要。趋化因子（或趋化因子）通过G蛋白偶联受体（gpcr）发出信号，调节血管生成，但尚未像其他血管生成因子那样深入研究，并且介导趋化因子调节血管生成的受体尚不清楚。基于GPCR可能形成异源二聚体有效信号传导的发现，我假设介导CXC趋化因子血管生成作用的GPCR （Ang-GPCR）是CXCR4的异源二聚体，基质衍生因子-1 （SDF-1）的GPCR和趋化因子的Duffy抗原受体DARC尚未显示信号，但可以结合CXC趋化因子。我将追求的具体目标是：#1证明在适当的条件下功能性的Ang-GPCR在内皮细胞上表达，并确定由Ang-GPCR介导的细胞反应。#2共表达DARC和CXCR4，证明形成了具有Ang-GPCR信号特征的受体。#3表明Ang-GPCR是DARC和CXCR4的异源二聚体。#4表明基质细胞衍生因子-1 （SDF-1）是CXCR4的激动剂，KC基因产物（KC）是与DARC结合的生长相关癌基因α (GROalpha)的小鼠同源物，是小鼠Ang-GPCR的共刺激配体。因为gpcr是很好的药物靶点，我建议如果我证明DARC和CXCR4的异源二聚体是Ang-GPCR，那么这个受体将是血管生成治疗的一个很好的靶点。

Angiogenesis is critical during development and pregnancy, for wound healing, and for revascularization of ischemic tissues and tumorigenesis. Chemotactic cytokines (or chemokines), which signal via G protein- coupled receptors (GPCRs), regulate angiogenesis but have not been studied as intensively as other angiogenic factors and the receptor that mediates chemokine regulation of angiogenesis is not known. Based on he findings that GPCRs may form heterodimers for effective signaling, I hypothesize that the GPCR that mediates the angiogenic effects of CXC chemokines (Ang-GPCR), is a heterodimer of CXCR4, the GPCR for stromal-derived factor-1 (SDF-1), and DARC, the Duffy antigen-receptor for chemokines that has not been shown to signal but that binds CXC chemokines. The Specific Aims that I will pursue are: #1 To show that functional Ang-GPCRs are expressed on endothelial cells under appropriate conditions and determine the cellular responses mediated by Ang-GPCR. #2 To co-express DARC and CXCR4 and demonstrate that a receptor that exhibits the signaling characteristics of Ang-GPCR is formed. #3 To show that Ang-GPCR is a heterodimer of DARC and CXCR4. #4 To show that stromal cell-derived factor-1 (SDF-1), which is an agonist at CXCR4, and the KC gene product (KC), which is the mouse homolog of growth-related oncogene alpha (GROalpha) that binds to DARC, are co-stimulatory ligands for Ang-GPCR in mice. Because GPCRs are excellent drug targets, I suggest if I show that the heterodimer of DARC and CXCR4 is Ang-GPCR that this receptor would be an excellent target for angiogenic therapy.