Biasing CXCR3 Signaling to Modulate the Inflammatory Response

CXCR3是一种趋化因子受体(CKR)，通过调节T细胞在炎症中发挥重要作用 迁移和功能。尽管CXCR3在动脉粥样硬化、癌症 对于转移和炎症性肠病，目前还没有FDA批准的针对该受体的药物。 事实上，只有两种FDA批准的药物针对整个CKR家族，该家族由20个成员组成 调节炎症的几乎所有方面的受体。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和缺乏 关于它们如何调节免疫细胞功能的知识。因此，尽管它们在各种不同的 在疾病状态下，针对CKRs的药物存在严重的未得到满足的需求。这让人联想到最近的结果 在我的研究小组中，我们发现CXCR3、CXCL9、10和11的同源配体不 简单地作为受体的激动剂或拮抗剂，但在数量和质量上都产生不同的结果 信号。这是一个与生理相关的“偏向激动症”的例子，这是G的一个药理学特征。 蛋白偶联受体(GPCR)信号，其中同一受体的不同配体诱导不同的 影响它们与异源三聚体G蛋白或β-arrestin(βARR)适配器相互作用的受体构象 蛋白质，导致不同的生物产量。我们的发现表明，利用有偏见的 CXCR3的激动化作为开发针对疾病相关信号的新型药物的一种手段 同时将偏离目标的影响降至最低。在我们的初步研究中，我们已经确定了小分子 差异激活G蛋白和βARR，并在CXCR3产生不同的βARR构象。它也是 确定这些有偏见的激动剂(A)以不同的方式激活激酶和转录途径；以及(B) 在炎症性皮肤病的小鼠模型中有明显的影响，发现与 假设G蛋白和β受体在CXCR3介导的炎症反应中起不同的作用。 我们研究的长期目标是开发针对CKR信号的新型偏向激动剂。整体而言 因此，在本申请中概述的研究的目的是确定G蛋白-和 β受体介导的信号转导CXCR3介导的炎症反应。我们的中心假设是这些 平行通路对调节T细胞功能的细胞内信号通路有不同的贡献 和炎症。我们计划测试我们的假设，并通过以下方式实现此应用程序的目标 具体目的如下：(1)使用G蛋白和βARR偏向的CXCR3内源和小分子 激动剂识别CXCR3的偏向决定因素；(2)识别受βARRs和G调节的信号通路 CXCR3下游的蛋白质；以及(3)决定G蛋白或βARR介导的信号转导的基础 CXCR3介导的炎症反应。该项目探索了一种以CXCR3信号为目标的创新方法以帮助 开发一类具有显著治疗潜力的新型分子。

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.