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
基本信息
- 批准号:10360796
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAffinityAgeAgingAgonistAmericanAnti-Inflammatory AgentsAntioxidantsB Cell ProliferationBeta CellBindingBiological AssayCardiovascular DiseasesCell DeathCell SurvivalCell physiologyCellsCessation of lifeClinicalClone CellsConsensusCoupledCouplesCuesCyclic AMP-Dependent Protein KinasesDNADataDiabetes MellitusDinoprostoneEP4 receptorElectronic Health RecordFinancial compensationFunctional disorderG-Protein-Coupled ReceptorsGLP-I receptorGTP-Binding Protein alpha Subunits, GsGene ExpressionGenesGlycosylated hemoglobin AGoalsHumanImpairmentIncidenceIndividualLeadLigand BindingLigandsLinkMachine LearningMitogensMusNon-Insulin-Dependent Diabetes MellitusNon-Steroidal Anti-Inflammatory AgentsObesityOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhenotypePhospholipase CPlayPropertyProstaglandin InhibitionProstaglandinsProtein IsoformsProteomicsRNA SplicingReceptor ActivationRegulationRegulatory PathwayResourcesRoleSamplingSignal PathwaySignal TransductionStrokeTestingVariantVeteransWFDC2 geneantagonistbasecell dedifferentiationclinically relevantcytokinecytotoxicdb/db mousegenome sequencingglucagon-like peptide 1heart disease riskhigh throughput screeningimprovedindividual patientisletmouse modelnew therapeutic targetpancreatic islet functionpatient responsepersonalized approachphosphoproteomicsprecision medicinepredict responsivenesspreservationpreventprogramsreceptorreceptor expressionresponsescreeningtranscription factortreatment choicewhole genome
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Maureen A Gannon其他文献
Maureen A Gannon的其他文献
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{{ truncateString('Maureen A Gannon', 18)}}的其他基金
Functional interaction of transcriptional regulators in endocrine lineage specification
内分泌谱系规范中转录调节因子的功能相互作用
- 批准号:
10577702 - 财政年份:2023
- 资助金额:
-- - 项目类别:
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 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Manipulating islet GPCR activity to promote beta cell proliferation and survival
操纵胰岛 GPCR 活性促进 β 细胞增殖和存活
- 批准号:
10453748 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Manipulating islet GPCR activity to promote beta cell proliferation and survival
操纵胰岛 GPCR 活性促进 β 细胞增殖和存活
- 批准号:
10022326 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Manipulating islet GPCR activity to promote beta cell proliferation and survival
操纵胰岛 GPCR 活性促进 β 细胞增殖和存活
- 批准号:
10219238 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Pathways regulating adult pancreatic beta cell replication
调节成人胰腺β细胞复制的途径
- 批准号:
9241554 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Formation and maturation of endocrine pancreas progenitors
内分泌胰腺祖细胞的形成和成熟
- 批准号:
9197982 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Formation and maturation of endocrine pancreas progenitors
内分泌胰腺祖细胞的形成和成熟
- 批准号:
9056074 - 财政年份:2015
- 资助金额:
-- - 项目类别:
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