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: 10611349
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10611349
• 关键词: Address; Affect; Affinity; Age; Aging; Agonist; American; Anti-Inflammatory Agents; Antioxidants; Beta Cell; Binding; Biological Assay; Cardiovascular Diseases; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Clone Cells; Compensation; Consensus; Coupled; Couples; Cues; Cyclic AMP-Dependent Protein Kinases; DNA; Data; Diabetes Mellitus; Dinoprostone; EP4 receptor; Electronic Health Record; Functional disorder; G-Protein-Coupled Receptors; GLP-I receptor; 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; Phenotype; Phospholipase C; Play; Proliferating; Property; Prostaglandin Inhibition; Prostaglandins; Protein Isoforms; Proteomics; RNA Splicing; Receptor Activation; Regulation; Regulatory Pathway; Resources; Role; Sampling; Signal Pathway; Signal Transduction; Sorting; Stroke; Testing; Variant; Veterans; WFDC2 gene; antagonist; 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; pharmacologic; 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.

2型糖尿病（T2 D）影响近25%的美国退伍军人，其特征是功能性β细胞减少， 马萨诸塞州患有T2 D的个体患心脏病和中风的风险增加。T2 D的发病率增加 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（PGE 2）在肥胖和T2 D的情况下升高，并与β细胞减少有关。 功能PGE 2结合四种G蛋白偶联受体（GPCR），命名为E-前列腺素（EP）1-4。肠降血糖素 GLP-1还通过GPCR发挥其作用，GLP-1受体激动剂用于治疗T2 D。 然而，并不是每个患者都对这类药物有积极的反应，这可能是由于药物活性的增加。 这些个体的β细胞中的负调控途径。我们的实验室发现EP 3和EP 4的PGE 2 受体调节β细胞质量动力学。我们发现，药理学抑制EP 3或激活EP 4， 在小鼠和人胰岛中增强离体β细胞增殖和存活。因此，EP 3和EP 4播放 在β细胞中具有相反的作用，其中EP 3抑制和EP 4增强细胞功能。此外，我们的初步 db/db T2 D小鼠模型的研究表明，EP 3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。 EP 3受体的多种剪接变体存在于所有物种中。这些变体具有相同的配体结合 性质，但在其组成性、激动剂非依赖性活性方面不同，EP 3 γ亚型具有最多的 组成型活性。在小鼠和人胰岛中，EP 3表达随着年龄和T2 D而增加， 降低对β细胞有丝分裂原的反应。在小鼠中，我们发现EP 3 γ随着年龄的增长而高度上调。 组成性活性EP 3受体将不受诸如非甾体类抗炎药的策略的影响 （NSAID），其降低配体PGE 2的合成。我们将使用基于细胞的筛选策略来识别逆 阻断组成型EP 3活性的激动剂。全基因组测序和蛋白质组学将定义下游 EP 3和EP 4受体调节在db/db小鼠的β细胞和来自患有T2 D的人的胰岛中的作用。机 学习方法将用于将PGE 2/EP通路基因的表达与T2 D患者 表型并预测患者对GLP-1途径激动剂的反应性。独特的范德比尔特资源（德- 识别的电子健康记录和相关DNA样本）将用于评估NSAID使用和/或 预测较低的EP 3表达或较高的EP 4表达与较好的结果相关。我们假设 增加的EP 3活性损害β细胞的特性和补偿，导致功能性β细胞质量降低 以及在T2 D和衰老背景下对GLP-1受体活化的反应性降低。