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.

2型糖尿病（T2D）影响了几乎25％的美国退伍军人，其特征是功能性β细胞降低 大量的。 T2D患者患心脏病和中风的风险增加。 T2D的事件增加 随着年龄的增长，部分原因是β细胞随着年龄的增长而对增殖提示做出反应的能力下降。 在肥胖和T2D的情况下，前列腺素E2（PGE2）升高，与β细胞降低有关 功能。 PGE2结合了四个G蛋白质受体（GPCRS）设计的E-螺纹型（EP）1-4。增加 GLP-1还通过GPCR执行其效果，GLP-1受体的激动剂用于治疗T2D。 但是，并非每个患者对这类药物做出积极反应，这可能是由于 这些个体的β细胞中的负调节途径。我们的实验室发现EP3和EP4 PGE2 受体调节β细胞质量动力学。我们发现药物抑制EP3或EP4的激活 在小鼠和人类胰岛中增强β细胞增殖和生存。那是EP3和EP4播放 EP3抑制和EP4在β细胞中相反的作用，增强了细胞功能。此外，我们的初步 在T2D的DB/DB小鼠模型中的研究表明，EP3拮抗剂的全身治疗增强了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某些变化。 EP3受体的多种剪接变体都存在于所有物种中。这些变体具有相同的配体结合 特性，但在其本构的非激动剂非依赖性活性中不同，EP3γ同工型具有最多 小鼠中的构成活性。 EP3表达在小鼠和人类胰岛中随着年龄的年龄和T2D而增加，并且 在小鼠中，我们发现EP3γ随着年龄的增长而大大更新。 组成型活性EP3受体将不受非甾体类抗炎药等策略的影响 （NSAID）较低的配体合成，PGE2。我们将使用基于单元的筛选策略来识别逆 阻断本构EP3活性的激动剂。整个基因组测序和蛋白质组学将定义下游 EP3和EP4受体调节在具有T2D的人类的DB/DB小鼠和胰岛的β细胞中的影响。机器 学习方法将用于将PGE2/EP途径基因的表达与T2D患者相关联 表型并预测患者对GLP-1途径激动剂的反应。独特的范德比尔特资源（DE- 确定的电子健康记录和链接的DNA样品）将用于评估NSAID使用和/或 预测的较低的EP3表达或更高的EP4表达与更好的结果有关。我们假设 EP3活性的增加会损害β细胞的身份和补偿，导致功能性β细胞质量降低 在T2D和衰老的情况下，提高了对GLP-1受体激活的响应能力。