Intestinal G protein-coupled receptors (GPCRs): characterising gut GPCR-signalling with potential to treat colitis

肠道 G 蛋白偶联受体 (GPCR)：表征具有治疗结肠炎潜力的肠道 GPCR 信号

• 批准号: 2749785
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2749785
• 关键词: Intestinal; protein; coupled; receptors; GPCRs

Free fatty acid receptors (FFARs) are GPCRs known to be expressed in enteroendocrine cells and therefore likely to be involved in nutrient- and microbial metabolite signaling in the mammalian GI tract. FFA1 and FFA4 are co-activated by long-chain fatty acids (LCFAs) while FFA2 and FFA3 are preferentially co-stimulated by microbial-derived short chain fatty acids (SCFAs). The nonselectivity between these pairs of GPCRs is complicated further by other GPCRs with affinity for fatty acids. For example, SCFAs activate GPR109A (also known as HCA2; Husted et al 2017) as well as olfactory receptors Olf78 and Olf558 (Bellono et al 2017) making specific FFARs' function(s) challenging due to lack of selective ligands. Thus, the roles of this GPCR group remain obscure in terms of GI health and disease. Using commercially available tools, Cox et al have however partially characterized FFA1-4 signaling in healthy GI mucosae and established their effects on GI transit in mice (Forbes et al 2015; Moodaley et al 2017; Tough et al 2018). This has been achieved using a combination of proven electrophysiological in vitro methods (measuring vectorial epithelial ion transport and barrier function in parallel) and measuring changes in upper and lower GI transit (Tough et al 2011). Our in-depth understanding of neuro-epithelial signaling within the GI tract, has been critical too. Notably, we see similar pharmacology and cellular mechanisms for FFA2 & FFA3 activities in normal mouse and human colon (Tough et al 2018) indicating translation of this approach. Selective, potent FFAR ligands are now critical for continued progress. With Heptares, our combined understanding of GI signalling is allowing us to characterise mucosal dysfunctions induced by acute GI inflammation. To this end we will include the mild colitis dextran sulphate sodium (DSS) model which PhD student, Evans (in Cox lab) is showing currently, recapitulates aspects of colitis pathology observed in man, allowing us to test the protective potential of novel ligands in murine colitis. Heptares have via their proprietary GPCR-targeted STaRR technology (https://soseiheptares.com/about-sosei-heptares) produced structurally diverse, first-in-class FFA4 and GPR109A ligands as well as selective FFA1, FFA2 and FFA3 synthetic agonists, with therapeutic potential as modulators of GI immune responses (van Daal et al 2021). However, the relative drug potencies in defined GI regions are unknown. This project will utilise chosen ligands to establish their efficacies in mouse GI tract allowing clear functional significance of their target GPCR to be identified. Heptares collaborate with a CRO (Selvita, in Zagreb, Croatia) who provide pathological validation of different rodent animal models of IBD. We benefit from this established relationship and Evans (LiDO student in year 3) will be working in Heptares to complete the scoring of low dose DSS-induced mucosal inflammation. Our proposal will establish therapeutic utility and ligand bioavailability for GI efficacy in vivo, thus contributing understanding of a new potential therapy for the unmet need of ulcerative colitis treatments. AIMS: i) to establish the efficacy of first-in-class compounds for gastrointestinal (GI) G protein-coupled receptors (GPCRs) and, ii) to characterise pathways that protect and/or reverse colitis in a mouse model.

游离脂肪酸受体（FFAR）是已知在肠内分泌细胞中表达的GPCR，因此可能参与哺乳动物胃肠道中的营养物质和微生物代谢物信号传导。FFA 1和FFA 4被长链脂肪酸（LCFA）共激活，而FFA 2和FFA 3优先被微生物来源的短链脂肪酸（SCFA）共刺激。这些GPCR对之间的非选择性被其他对脂肪酸具有亲和力的GPCR进一步复杂化。例如，SCFA激活GPR 109 A（也称为HCA 2; Husted et al 2017）以及嗅觉受体Olf 78和Olf 558（Bellono et al 2017），由于缺乏选择性配体，使得特定FFAR的功能具有挑战性。因此，就胃肠道健康和疾病而言，这一群体的作用仍然模糊不清。然而，使用市售工具，考克斯et al对健康GI粘膜中的FFA 1 -4信号传导进行了部分表征，并确定了其对小鼠GI转运的影响（福布斯et al 2015; Moodaley et al 2017;坚韧et al 2018）。这是使用经证实的体外电生理学方法（平行测量矢量上皮离子转运和屏障功能）和测量上消化道和下消化道转运变化的组合实现的（坚韧et al 2011）。我们对胃肠道内神经上皮信号传导的深入了解也至关重要。值得注意的是，我们在正常小鼠和人结肠中观察到FFA 2和FFA 3活性的相似药理学和细胞机制（坚韧et al 2018），表明这种方法的转化。选择性的、有效的FFAR配体现在对于持续的进展至关重要。对于Hepatitis，我们对GI信号传导的综合理解使我们能够消除急性GI炎症引起的粘膜功能障碍。为此，我们将包括轻度结肠炎葡聚糖硫酸钠（DSS）模型，该模型是博士生Evans（考克斯实验室）目前正在展示的，概括了在人类中观察到的结肠炎病理学方面，使我们能够测试新型配体在鼠结肠炎中的保护潜力。Heparin通过其专有的GPCR靶向STaRR技术（https：//soseiheptares.com/about-sosei-heparin）生产了结构多样的一流FFA 4和GPR 109 A配体以及选择性FFA 1、FFA 2和FFA 3合成激动剂，具有作为GI免疫应答调节剂的治疗潜力（货车Daal et al 2021）。然而，在定义的GI区域的相对药物效力是未知的。该项目将利用选定的配体来确定其在小鼠胃肠道中的功效，从而确定其靶GPCR的明确功能意义。Hepatrium与CRO（Selvita，Zagreb，Croatia）合作，后者提供IBD的不同啮齿动物模型的病理学验证。我们从这种建立的关系中受益，Evans（LiDO 3年级学生）将在Hepatitis中工作，以完成低剂量DSS诱导的粘膜炎症评分。我们的建议将建立治疗效用和配体生物利用度的胃肠道疗效在体内，从而有助于了解一种新的潜在的治疗溃疡性结肠炎治疗的未满足的需求。目标：i）确定一类化合物对胃肠道（GI）G蛋白偶联受体（GPCR）的功效，和ii）阻断保护和/或逆转小鼠模型中结肠炎的途径。