Regulation of chemokine receptor signaling

趋化因子受体信号传导的调节

• 批准号: 10622915
• 负责人: Adriano Marchese
• 金额: $ 25.03万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622915
• 关键词: A kinase anchoring protein; Address; Automobile Driving; Biochemical; Biological Assay; Biophysics; CXC Chemokines; Cell Culture Techniques; Cessation of life; Confocal Microscopy; Disease; Embryonic Development; Family; Fluorescence; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Knowledge; Label; Ligation; Malignant Neoplasms; Modeling; Molecular; Physiological Processes; Play; Prognosis; Receptor Signaling; Regulation; Research; Role; Signal Transduction; Therapeutic; Translating; beta-arrestin; chemokine receptor; drug discovery; human disease; immune function; innovation; live cell imaging; novel; receptor; receptor binding; reconstitution; stem cells; structural determinants; therapeutic development

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.

项目摘要 G蛋白偶联受体（GPCR）信号在许多物理过程中起着至关重要的作用，也是 涉及许多人类疾病，但是管理GPCR信号的机制仍然鲜为人知。 拟议的研究的目的是进一步我们对GPCR信号传导的理解。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信号传导 除其他功能外，对于胚胎发生，免疫功能和干细胞调节非常重要。此外， CXCR4信号传导参与包括癌症在内的几种人类疾病。 CXCR4异常表达 许多癌症及其表达与预后不良相关。这主要是因为CXCR4信号传导 导致转移性疾病，这是大多数与癌症相关的死亡的原因。然而机制管理 CXCR4信号传导仍然鲜为人知。为了实现我们的目标，我们将解决两个主要问题：1。 是通过非GPCR结合驱动β-urrestin的生物物理和结构决定剂驱动GPCR信号 伙伴？ 2。在分室化中，PKCD和A-激酶锚定蛋白（AKAP）的作用是什么 GPCR信号的异源调节？为了解决这些问题，我们将主要使用细胞培养模型 并使用几种免费的综合方法进行重构测定，包括生物物理， 生化，接近连接，多标签荧光共聚焦显微镜，活细胞成像和信号传导 测定。我们认为我们的研究很重要，因为我们期望定义广泛应用的新概念 在整个GPCR家族中，将提供对驱动GPCR信号传导的机制的高级解释。 我们的研究有望将新知识转化为创新的药物发现努力以调节 GPCR信号治疗。