Modulating prostaglandin E2 receptor activity to improve pancreatic islet function

调节前列腺素 E2 受体活性以改善胰岛功能

• 批准号: 10360796
• 负责人: Maureen A Gannon
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360796
• 关键词: Address; Affect; Affinity; Age; Aging; Agonist; American; Anti-Inflammatory Agents; Antioxidants; B Cell Proliferation; Beta Cell; Binding; Biological Assay; Cardiovascular Diseases; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Clone Cells; Consensus; Coupled; Couples; Cues; Cyclic AMP-Dependent Protein Kinases; DNA; Data; Diabetes Mellitus; Dinoprostone; EP4 receptor; Electronic Health Record; Financial compensation; Functional disorder; G-Protein-Coupled Receptors; GLP-I receptor; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genes; Glycosylated hemoglobin A; Goals; Human; Impairment; Incidence; Individual; Lead; Ligand Binding; Ligands; Link; Machine Learning; Mitogens; Mus; Non-Insulin-Dependent Diabetes Mellitus; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phospholipase C; Play; Property; Prostaglandin Inhibition; Prostaglandins; Protein Isoforms; Proteomics; RNA Splicing; Receptor Activation; Regulation; Regulatory Pathway; Resources; Role; Sampling; Signal Pathway; Signal Transduction; Stroke; Testing; Variant; Veterans; WFDC2 gene; antagonist; base; cell dedifferentiation; clinically relevant; cytokine; cytotoxic; db/db mouse; genome sequencing; glucagon-like peptide 1; heart disease risk; high throughput screening; improved; individual patient; islet; mouse model; new therapeutic target; pancreatic islet function; patient response; personalized approach; phosphoproteomics; precision medicine; predict responsiveness; preservation; prevent; programs; receptor; receptor expression; response; screening; transcription factor; treatment choice; whole genome

Type 2 diabetes (T2D) affects nearly 25% of US veterans and is characterized by decreased functional β-cell mass. Individuals with T2D have increased risk for heart disease and stroke. The incidence of T2D increases with age, in part due to a decreased ability of β cells to respond to proliferative cues as they get older. Prostaglandin E2 (PGE2) is elevated in the setting of obesity and T2D and is associated with decreased β-cell function. PGE2 binds four G protein-couple receptors (GPCRs) designated E-Prostanoid (EP)1-4. The incretin GLP-1 also exerts its effects through a GPCR and agonists of the GLP-1 receptor are used to treat T2D. However, not every patient responds positively to this class of drugs, potentially due to increased activity of negative regulatory pathways in the β cells of these individuals. Our lab discovered that the EP3 and EP4 PGE2 receptors modulate β-cell mass dynamics. We found that pharmacological inhibition of EP3 or activation of EP4 enhances β-cell proliferation and survival in both mouse and human islets ex vivo. Thus, EP3 and EP4 play opposing roles in β cells with EP3 inhibiting and EP4 enhancing cellular functions. In addition, our preliminary studies in the db/db mouse model of T2D reveal that systemic treatment with EP3 antagonist enhances β-cell proliferation and mass and reverses some of the changes in gene expression associated with β-cell dysfunction. Multiple splice variants of the EP3 receptor exist in all species. These variants have identical ligand binding properties, but differ in their constitutive, agonist-independent activity, with the EP3γ isoform having the most constitutive activity in mouse. EP3 expression increases with age and T2D in mouse and human islets and decreases in response to β-cell mitogens. In mice, we found that EP3γ is most highly upregulated with age. Constitutively active EP3 receptor would be unaffected by strategies such as non-steroidal anti-inflammatories (NSAIDs) that lower synthesis of the ligand, PGE2. We will use a cell-based screening strategy to identify inverse agonists that block constitutive EP3 activity. Whole genome sequencing and proteomics will define downstream effects of EP3 and EP4 receptor modulation in β cells of db/db mice and islets from humans with T2D. Machine learning approaches will be used to correlate expression of PGE2/EP pathway genes with T2D patient phenotypes and to predict patient responsiveness to GLP-1 pathway agonists. Unique Vanderbilt resources (de- identified electronic health record and linked DNA samples) will be used to assess whether NSAID use and/or predicted lower EP3 expression or higher EP4 expression is associated with better outcomes. We hypothesize that increased EP3 activity impairs β-cell identity and compensation leading to decreased functional β-cell mass and decreased responsiveness to GLP-1 receptor activation in the setting of T2D and aging.

近 25% 的美国退伍军人患有 2 型糖尿病 (T2D)，其特点是功能性 β 细胞减少 大量的。患有 T2D 的人患心脏病和中风的风险增加。 T2D 发病率增加 随着年龄的增长，部分原因是随着年龄的增长，β细胞对增殖信号的反应能力下降。 前列腺素 E2 (PGE2) 在肥胖和 T2D 情况下升高，并与 β 细胞减少相关 功能。 PGE2 结合四种 G 蛋白偶联受体 (GPCR)，称为 E-前列腺素 (EP)1-4。肠促胰岛素 GLP-1 还通过 GPCR 发挥作用，GLP-1 受体激动剂用于治疗 T2D。 然而，并非每个患者都对此类药物产生积极反应，这可能是由于 这些个体的β细胞中存在负调节途径。我们的实验室发现 EP3 和 EP4 PGE2 受体调节 β 细胞质量动力学。我们发现药理学上抑制EP3或激活EP4 增强小鼠和人类胰岛离体 β 细胞的增殖和存活。因此，EP3和EP4播放 β 细胞中的 EP3 抑制作用和 EP4 增强细胞功能相反的作用。此外，我们初步 T2D db/db 小鼠模型研究表明，EP3 拮抗剂全身治疗可增强 β 细胞 增殖和质量，并逆转与 β 细胞功能障碍相关的基因表达的一些变化。 所有物种中都存在 EP3 受体的多种剪接变体。这些变体具有相同的配体结合 性质，但其组成型、不依赖激动剂的活性不同，其中 EP3γ 亚型具有最多的活性 小鼠的组成型活性。小鼠和人类胰岛中 EP3 的表达随着年龄和 T2D 的增加而增加 对 β 细胞有丝分裂原的反应减少。在小鼠中，我们发现 EP3γ 随着年龄的增长而上调程度最高。 组成型活性 EP3 受体不会受到非甾体类抗炎药等策略的影响 (NSAID) 会降低配体 PGE2 的合成。我们将使用基于细胞的筛选策略来识别逆 阻断 EP3 组成型活性的激动剂。全基因组测序和蛋白质组学将定义下游 EP3 和 EP4 受体调节对 db/db 小鼠的 β 细胞和患有 T2D 的人类胰岛的影响。机器 学习方法将用于将 PGE2/EP 通路基因的表达与 T2D 患者相关联 表型并预测患者对 GLP-1 通路激动剂的反应。独特的范德比尔特资源（de- 已识别的电子健康记录和关联的 DNA 样本）将用于评估是否使用 NSAID 和/或 预测较低的 EP3 表达或较高的 EP4 表达与更好的结果相关。我们假设 EP3 活性增加会损害 β 细胞身份和补偿，导致功能性 β 细胞质量减少 在 T2D 和衰老的情况下，对 GLP-1 受体激活的反应性降低。