CXC chemokine receptors, angiogenesis and angiostasis

血管生成在发育和妊娠期间、对于伤口愈合、以及对于缺血组织的再血管化和肿瘤发生是至关重要的。通过G蛋白偶联受体（GPCR）发出信号的趋化性细胞因子（或趋化因子）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未知。基于GPCR可以形成异源二聚体用于有效信号传导的发现，我假设介导CXC趋化因子的血管生成作用的GPCR（Ang-GPCR）是CXCR 4的异源二聚体，CXCR 4是基质衍生因子-1（SDF-1）的GPCR，DARC是尚未显示出信号传导但结合CXC趋化因子的趋化因子的Duffy抗原受体。我将追求的具体目标是：#1显示功能性Ang-GPCR在适当条件下在内皮细胞上表达，并确定Ang-GPCR介导的细胞反应。#2共表达DARC和CXCR 4，并证明形成了表现Ang-GPCR信号特征的受体。#3显示Ang-GPCR是DARC和CXCR 4的异二聚体。#4显示基质细胞衍生因子-1（SDF-1）（CXCR 4激动剂）和KC基因产物（KC）（生长相关癌基因α（GRO α）的小鼠同源物，与DARC结合）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CXCR 4的异源二聚体是Ang-GPCR，那么这个受体将是血管生成治疗的很好靶点。

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.