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

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

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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:
Regulation of adult pancreatic beta cell replication
成人胰腺β细胞复制的调节
  • 批准号:
    8140822
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Regulation of adult pancreatic beta cell replication
成人胰腺β细胞复制的调节
  • 批准号:
    8244927
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

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