Biasing CXCR3 Signaling to Modulate the Inflammatory Response

偏置 CXCR3 信号传导来调节炎症反应

• 批准号: 9447055
• 负责人: Sudarshan K Rajagopal
• 金额: $ 30.89万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447055
• 关键词: Adaptor Signaling Protein; Agonist; Atherosclerosis; Biological; CXCL9 gene; CXCR3 gene; Cell physiology; Characteristics; Chemotaxis; Development; Disease; Drug Targeting; Event; FDA approved; Family; G Protein-Coupled Receptor Signaling; G protein coupled receptor kinase; G-substrate; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genetic Transcription; Goals; Heterotrimeric GTP-Binding Proteins; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Knowledge; Ligands; Malignant Neoplasms; Mediating; Modeling; Molecular Conformation; Neoplasm Metastasis; Output; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Receptor Signaling; Recruitment Activity; Research; Role; Signal Pathway; Signal Transduction; Site; Skin; T cell regulation; T-Lymphocyte; Testing; Therapeutic; Transcript; Work; beta-arrestin; cell motility; cell type; chemokine; chemokine receptor; clinically relevant; cytokine; drug development; in vitro testing; innovation; knock-down; mouse model; novel; novel drug class; receptor; response; skin disorder; small molecule; trafficking; transcription factor

CXCR3 is a chemokine receptor (CKR) that plays a central role in inflammation through its regulation of T cell migration and function. Despite the established clinical relevance of CXCR3 in atherosclerosis, cancer metastasis and inflammatory bowel disease, there are no FDA-approved drugs that target this receptor. Indeed, there are only two FDA approved drugs that target the entire CKR family, which consists of twenty receptors that regulate nearly every aspect of inflammation. Reasons for the difficulty in drug development at CKRs include the potential redundancy between multiple cognate chemokine ligands for each CKR and a lack of knowledge regarding how they regulate immune cell function. Thus, despite their central role in a variety of disease states, there is a critical unmet need for drugs targeting CKRs. This puts into context recent results from my group in which we have discovered that the cognate ligands of CXCR3, CXCL9, 10 and 11, do not simply act as agonists or antagonists at the receptor, but generate both quantitatively and qualitatively distinct signals. This is a physiologically relevant example of “biased agonism”, a pharmacologic characteristic of G protein-coupled receptor (GPCR) signaling, in which different ligands for the same receptor induce distinct receptor conformations that impact their interaction with heterotrimeric G proteins or β-arrestin (βarr) adapter proteins, resulting in different biological outputs. Our findings suggest that it will be possible to exploit biased agonism at CXCR3 as a means to develop new classes of drugs that target disease-relevant signaling pathways while minimizing off-target effects. In our preliminary studies, we have identified small molecules that differentially activate G proteins and βarrs and generate distinct βarr conformations at CXCR3. It was also determined that these biased agonists (a) differentially activate kinases and transcriptional pathways; and (b) have distinct effects in a mouse model of inflammatory skin disease, findings that are consistent with the hypothesis that G proteins and βarrs differentially contribute to the CXCR3-mediated inflammatory response. The long-term goal of our research is to develop novel biased agonists targeting CKR signaling. The overall objective of the studies outlined in this application, therefore, is to identify the contributions of G protein- and βarr-mediated signaling to CXCR3-mediated inflammatory responses. Our central hypothesis is that these parallel pathways differentially contribute to the intracellular signaling pathways that regulate T cell function and inflammation. We plan to test our hypothesis and accomplish the objectives of this application by pursuing the following specific aims: (1) Use G protein- and βarr-biased CXCR3 endogenous and small molecule agonists to identify determinants of bias at CXCR3; (2) Identify signaling pathways regulated by βarrs and G proteins downstream of CXCR3; and (3) Determine how G protein- or βarr-mediated signaling underlies CXCR3-mediated inflammation. This project explores an innovative approach to target CXCR3 signaling to aid in the development of a novel class of molecules with significant therapeutic potential.

CXCR3是一种趋化因子受体（CKR），通过调节T细胞在炎症中起着核心作用 迁移和功能。尽管CXCR3在动脉粥样硬化中建立了临床相关性，但癌症仍在 转移和炎症性肠病，没有针对该接收器的FDA批准药物。 确实，只有两种FDA批准的药物针对整个CKR家族，其中包括二十个 几乎调节炎症的各个方面的受体。在药物开发困难的原因 CKR包括每个CKR的多个同源趋化因子配体之间的潜在冗余，而缺乏 关于它们如何调节免疫细胞功能的知识。那是他们在各种各样的核心角色 疾病状态下，对针对CKR的药物有至关重要的未满足需求。这使得最新结果 从我的小组中，我们发现CXCR3，CXCL9、10和11的同源配体 只需充当接收器的激动剂或拮抗剂，但在定量和定性上产生 信号。这是“偏见激动剂”的物理相关例子，这是G的药物特征 蛋白质偶联受体（GPCR）信号传导，其中相同受体的不同配体诱导不同 影响其与异源三聚体G蛋白或β-arrestin（βARR）适配器相互作用的受体构象 蛋白质，导致不同的生物输出。我们的发现表明，有可能探索有偏见 CXCR3的激动剂是开发针对疾病信号传导的新型药物的一种手段 途径同时最大程度地减少脱靶效应。在我们的初步研究中，我们已经确定了小分子 不同地激活G蛋白和βARRR，并在CXCR3处产生不同的βarr构象。也是 确定这些偏见的激动剂（a）不同地激活激酶和转录途径。 （b） 在炎症性皮肤病的小鼠模型中具有明显的影响，与 假设G蛋白和βARR对CXCR3介导的炎症反应有所不同。 我们研究的长期目标是开发针对CKR信号的新型偏见的激动剂。总体 因此，本应用中概述的研究的目的是确定G蛋白和G蛋白和 βARR介导的信号传导对CXCR3介导的炎症反应。我们的中心假设是 平行途径对调节T细胞功能的细胞内信号通路有所不同 和炎症。我们计划通过追求来检验我们的假设并实现此应用的目标 以下特定目的：（1）使用G蛋白质和βARR偏置的CXCR3内源性和小分子 激动剂识别CXCR3偏差的决定者； （2）识别由βarr和g调节的信号通路 CXCR3下游的蛋白质； （3）确定G蛋白或βArr介导的信号传导的基础 CXCR3介导的炎症。该项目探讨了一种创新的方法来靶向CXCR3信号以帮助 在开发具有显着治疗潜力的新型分子中。