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.

项目概要 G 蛋白偶联受体 (GPCR) 信号在许多生理过程中发挥着重要作用，并且 GPCR 与许多人类疾病有关，但人们对 GPCR 信号传导的机制仍知之甚少。 本研究的目的是加深我们对 GPCR 信号传导模型的机制理解。 我们研究的 GPCR 受体是治疗相关的 C-X-C 趋化因子受体 4 (CXCR4)。 对于胚胎发生、免疫功能和干细胞调节等功能很重要。 CXCR4 信号传导涉及多种人类疾病，包括癌症中 CXCR4 的异常表达。 许多癌症及其表达与不良预后相关，这主要是因为 CXCR4 信号传导。 导致转移性疾病，这是大多数癌症相关死亡的原因。 CXCR4 信号传导仍然知之甚少，为了实现我们的目标，我们将解决两个主要问题： 1. 什么。 是通过非 GPCR 结合驱动 β-arrestins 发出 GPCR 信号的生物物理和结构决定因素 2. PKCd 和 A-激酶锚定蛋白 (AKAP) 在区室化中的作用是什么？ 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 和重构测定使用几种互补的综合方法，包括生物物理、 生物化学、邻近连接、多标记荧光共聚焦显微镜、活细胞成像和信号传导 我们相信我们的研究意义重大，因为我们期望定义广泛适用的新概念。 整个 GPCR 家族，这将为驱动 GPCR 信号传导的机制提供高级解释。 我们的研究有望将新知识转化为创新药物发现工作，以调节 GPCR 信号传导治疗。