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.
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
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)
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:
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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