Molecular Pharmacology of the Lipid/pH-sensing GPCRs as modulators of immune cell function

脂质/pH敏感受体家族是由四个G蛋白偶联受体(GPCRs)组成的簇，在免疫细胞功能和癌细胞增殖中发挥作用。它们对不同生理环境中微环境变化引起的脂质介质水平和/或pH的变化做出反应。这个家族的成员存在于单核细胞和巨噬细胞等细胞中，但关于它们如何调节炎症反应的信息有限。本项目旨在通过定义它们如何利用最近发展的细胞内生物传感器来参与不同的细胞内信号通路来控制细胞反应，从而增加我们对这些GPCRs的基本理解。最初，这些GPCRs将使用模型细胞系统进行研究，但观察将扩展到与生理相关的环境，包括替代单核细胞样细胞系和单核/巨噬细胞的原代培养。新疗法开发中的一个主要挑战是确定推动其生理效应的药物的分子机制。在历史上的药物发现中，当候选化合物进入临床测试时，这一差距往往无法弥合，从而增加了失败的可能性。一种新的方法是生成许多不同参数的数据矩阵，并利用建模和/或AI/ML数据分析方法来确定疗效的预测因素。学生将利用现有的实验方法以及内部的分析支持，为从脂质/酸碱度传感家族中选择的GPCR建立一个数据矩阵。

The Lipid/pH-sensing receptor family are a cluster of four G protein coupled receptors (GPCRs) with roles in immune cell function and cancer cell proliferation1. They respond to changes in levels of lipid mediators and/or pH caused by microenvironmental changes in different physiological contexts. Members of this family are present in cells such as monocytes and macrophages but only limited information is available concerning how they modulate the inflammatory response.This project aims to increase our fundamental understanding of these GPCRs by defining how they engage different intracellular signalling pathways to control cellular responses, using recently developed intracellular biosensors. Initially, these GPCRs will be studied using model cell systems but observations will be extended to physiologically-relevant contexts including surrogate monocyte-like cell lines and primary cultures of monocytes/macrophages.A major challenge in the development of new therapies is to define the molecular mechanisms of drugs that drive their physiological effect. In historical drug discovery, this gap is often unresolved when candidate compounds enter clinical testing, increasing the likelihood of failure. A new approach is to generate matrices of data across many different parameters, and to harness modelling and/or AI/ML data analytic approaches to identify predictors of efficacy. The student will utilise available experimental approaches along with in house analytical support to build a data matrix for a chosen GPCR from the lipid/pH-sensing family.