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）影响了近25%的美国退伍军人，其特征是功能性β细胞减少