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:10611349
- 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 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAgeAgingAgonistAmericanAnti-Inflammatory AgentsAntioxidantsBeta CellBindingBiological AssayCardiovascular DiseasesCell DeathCell ProliferationCell SurvivalCell physiologyCellsCessation of lifeClinicalClone CellsCompensationConsensusCoupledCouplesCuesCyclic AMP-Dependent Protein KinasesDNADataDiabetes MellitusDinoprostoneEP4 receptorElectronic Health RecordFunctional disorderG-Protein-Coupled ReceptorsGLP-I receptorGene ExpressionGenesGlycosylated hemoglobin AGoalsHumanImpairmentIncidenceIndividualLeadLigand BindingLigandsLinkMachine LearningMitogensMusNon-Insulin-Dependent Diabetes MellitusNon-Steroidal Anti-Inflammatory AgentsObesityOutcomePathway interactionsPatientsPharmaceutical PreparationsPhenotypePhospholipase CPlayProliferatingPropertyProstaglandin InhibitionProstaglandinsProtein IsoformsProteomicsRNA SplicingReceptor ActivationRegulationRegulatory PathwayResourcesRoleSamplingSignal PathwaySignal TransductionSortingStrokeTestingVariantVeteransWFDC2 geneantagonistcell dedifferentiationclinically relevantcytokinecytotoxicdb/db mousegenome sequencingglucagon-like peptide 1heart disease riskhigh throughput screeningimprovedindividual patientisletmouse modelnew therapeutic targetpancreatic islet functionpatient responsepersonalized approachpharmacologicphosphoproteomicsprecision 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.
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-
确定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。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
10360796 - 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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