Regulation of chemokine receptor signaling

项目总结 G蛋白偶联受体(Gpr)信号在许多生理过程中起着重要作用，也是 参与了许多人类疾病，但GPCR信号转导的机制仍然知之甚少。 这项研究的目的是为了加深我们对GPCR信号的机制的理解。模型 我们研究的GPCR受体是与治疗相关的C-X-C趋化因子受体4(CXCR4)。CXCR4信号转导 对胚胎发育、免疫功能和干细胞调节等功能都很重要。此外, CXCR4信号与包括癌症在内的几种人类疾病有关。CXCR4在卵巢癌中异常表达 许多癌症及其表达与预后不良有关。这主要是因为CXCR4信号 导致转移性疾病，这是大多数癌症相关死亡的原因。然而，治理的机制 CXCR4信号仍然知之甚少。为了实现我们的目标，我们将解决两个主要问题：1.什么 生物物理和结构决定因素是否是通过非β结合的抑制素驱动gpr信号转导的？ 伴侣？2.PKCd和A-激酶锚定蛋白(AKAPs)在脑区隔化中的作用 GPCR信号的异源调控？为了解决这些问题，我们将主要使用细胞培养模型 以及使用几种互补的综合方法的重建分析，包括生物物理， 生化、邻近连接、多标记荧光共聚焦显微镜、活细胞成像和信号转导 化验。我们相信我们的研究是有意义的，因为我们希望定义广泛适用的新概念 这将为驱动GPCR信号转导的机制提供高级解释。 我们的研究承诺将新知识转化为创新的药物发现努力，以调节 GPCR信号转导治疗。

PROJECT SUMMARY G protein-coupled receptor (GPCR) signaling plays an essential role in many physiological processes and is also involved in many human diseases, yet the mechanisms governing GPCR signaling remain poorly understood. The goal of the proposed research is to further our mechanistic understanding of GPCR signaling. The model GPCR receptor we study is the therapeutically relevant C-X-C chemokine receptor 4 (CXCR4). CXCR4 signaling is important for embryogenesis, immune function and stem cell regulation, among other functions. In addition, CXCR4 signaling is involved in several human diseases, including cancer. CXCR4 is aberrantly expressed in many cancers and its expression correlates with poor prognosis. This is mainly because CXCR4 signaling contributes to metastatic disease, the reason for most cancer related deaths. Yet the mechanisms governing CXCR4 signaling remain poorly understood. To achieve our goal, we will address two main questions: 1. What are the biophysical and structural determinants driving GPCR signaling by β-arrestins via non-GPCR binding partners? 2. What are the roles of PKCd and A-kinase anchoring proteins (AKAPs) in compartmentalized heterologous regulation of GPCR signaling? To address these questions, we will mainly use cell culture models and reconstitution assays using several complimentary integrative approaches including biophysical, biochemical, proximity ligation, multi-labeling fluorescence confocal microscopy, live cell imaging, and signaling assays. We believe our research is significant because we expect to define new concepts that apply broadly across the GPCR family, which will provide an advanced explanation of the mechanisms driving GPCR signaling. Our research hold the promise to translate new knowledge into innovative drug discovery efforts to modulate GPCR signaling therapeutically.