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

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:
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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