Role of the Renin-Angiotensin System in Glucose Homeostasis
Role of the Renin-Angiotensin System in Glucose Homeostasis
批准号:
10665042
负责人:
Sakeneh Zraika
金额:
$39.05万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-14 至 2026-05-31
关键词:
AddressAdolescentAdultAnabolismAngiotensinsAntidiabetic DrugsApoptosisBeta CellBindingCRISPR/Cas technologyCell DeathCell ProliferationCell SurvivalCell physiologyCellsClinical ManagementDataDeteriorationDevelopmentDiabetic mouseDipeptidesDiphtheria ToxinExposure toFailureFutureGLP-I receptorGPRC6A geneGenetic TranscriptionGlucagonGlucoseGoalsHumanHydrolysisIn VitroInhibition of ApoptosisInsulinInvestigationIslets of Langerhans TransplantationKnock-outMediatingModelingMusMutagenesisNatural regenerationNon-Insulin-Dependent Diabetes MellitusOutputParacrine CommunicationPharmaceutical PreparationsPrevalenceProductionProliferatingPropertyProteinsPublic HealthRenin-Angiotensin SystemResearchResistanceRoleSignal PathwaySignal TransductionStructure of beta Cell of isletTestingTherapeuticTherapeutic InterventionTimeWithdrawalYouthactive methodage relatedblood glucose regulationcell regenerationdiabeticgain of functionglucagon-like peptide 1glycemic controlimprovedin vivoinhibitorinnovationinsulin secretionisletloss of functionnew therapeutic targetnon-diabeticnovelparacrinephosphoproteomicspreservationpreventproglucagonprotective effecttargeted treatmenttherapeutic developmenttransplant model
中文摘要
项目总结/摘要
在治疗2型糖尿病(T2 D)时,缺乏同时靶向两种缺陷的药物。
β细胞功能和质量。血管紧张素(1-7),肾素-血管紧张素系统的代谢产物,可能填补这一空白;
然而,其潜在的作用机制尚未完全了解。我们的数据显示,
血管紧张素(1-7)的促胰岛素作用依赖于其水解为二肽血管紧张素(1-2),
后者还在β细胞中传递促存活和增殖作用。血管紧张素(1-2)激活G蛋白-
偶联受体家族C组6成员A(GPRC 6A),我们显示其在胰岛a细胞中表达。此外,本发明还
血管紧张素(1-2)增加细胞源性胰高血糖素样肽-1(GLP-1)的释放,表明其通过
GPRC 6A在α细胞上以旁分泌方式促进胰岛素分泌。事实上,在GLP-1受体缺陷的情况下,
我们发现,血管紧张素(1-2)不能增强胰岛素分泌,但其增强胰岛β细胞分泌的能力,
存活和增殖得以保留。后者表明血管紧张素(1-2)的作用部分是GLP-1受体,
独立的基于这些新数据,我们假设血管紧张素(1-2)通过细胞内增强β细胞功能
胰岛旁分泌信号传导,并通过新的GLP-1非依赖性机制促进β细胞存活/增殖。
以下具体目标解决了这一假设,目的是改善T2 D的治疗选择:
具体目标1。确定血管紧张素(1-2)增加胰岛源性GLP-1的机制
和胰岛素分泌。小鼠(体内)和胰岛(体外)与白喉毒素诱导的a细胞破坏或a
将使用细胞特异性GPRC 6A敲除来确定血管紧张素(1-2)介导的GPRC 6A表达增加是否与血管紧张素(1-2)介导的GPRC 6A表达增加有关。
胰岛素释放分别需要α细胞或α-细胞GPRC 6A。我们将探索GLP-1增加的机制,
释放,并确认在有和没有GLP-1受体或GPRC 6A阻断的人胰岛中的关键发现。
具体目标2。鉴定介导β细胞存活和增殖的信号通路/蛋白质
Ang(1-2)在人胰岛中的作用血管紧张素(1-2)抑制细胞凋亡、减少细胞凋亡的能力,
将在非糖尿病条件下的人胰岛中检查β细胞的去分化和增强增殖,
糖尿病状况。将确定独立于GLP-1或GPRC 6A的机制的贡献。
血管紧张素(1-2)作用的效应物将使用无偏倚磷酸蛋白质组学鉴定,然后使用磷酸化蛋白质组学的缺失/获得来鉴定。
胰岛功能研究将作为治疗靶向效应物的初步筛选。
具体目标3。确定Ang(1-2)是否在体内改善人胰岛功能/存活,
Ang(1-7)的水解是否是其抗糖尿病作用所必需的。我们将利用人类的胰岛
移植模型,以确定血管紧张素(1-2)改善β细胞功能/存活和血管紧张素(1 - 2)
糖尿病小鼠此外,我们将测试血管紧张素(1-7)的促胰岛素作用是否需要其水解,
如在体外的情况。后者对于T2 D的临床管理非常重要,因为它将告知
目前正在开发的抗水解血管紧张素(1-7)药物的效用。
英文摘要
PROJECT SUMMARY/ABSTRACT
In treating type 2 diabetes (T2D), there is a paucity of medications simultaneously targeting deficits in both
β-cell function and mass. Angiotensin(1-7), a metabolite of the renin-angiotensin system, may fill this gap;
however, its underlying mechanisms of action are incompletely understood. Our data reveal that the
insulinotropic action of angiotensin(1-7) is dependent on its hydrolysis to the dipeptide, angiotensin(1-2), the
latter also conveying pro-survival and proliferative effects in β cells. Angiotensin(1-2) activates G-protein-
coupled receptor family C group 6 member A (GPRC6A), which we show is expressed in islet a cells. Further,
angiotensin(1-2) increases a cell-derived glucagon-like peptide-1 (GLP-1) release, suggesting it acts via
GPRC6A on the a cell to promote insulin secretion in a paracrine fashion. Indeed, in GLP-1 receptor deficient
islets, we find that angiotensin(1-2) fails to potentiate insulin secretion; however, its ability to enhance β-cell
survival and proliferation is retained. The latter suggests angiotensin(1-2)’s action is, in part, GLP-1 receptor-
independent. Based on these novel data, we hypothesize angiotensin(1-2) enhances β-cell function via intra-
islet paracrine signaling, and promotes β-cell survival/proliferation via a novel GLP-1-independent mechanism.
The following specific aims address this hypothesis, with the goal of improving treatment options in T2D:
Specific Aim 1. To determine the mechanism by which angiotensin(1-2) increases islet-derived GLP-1
and insulin secretion. Mice (in vivo) and islets (in vitro) with diphtheria toxin-induced a-cell destruction or a
cell-specific GPRC6A knockout will be used to determine whether angiotensin(1-2)-mediated increases in
insulin release require a cells or a-cell GPRC6A, respectively. We will probe mechanisms for increased GLP-1
release, and confirm key findings in human islets with and without GLP-1 receptor or GPRC6A blockade.
Specific Aim 2. To identify signaling pathways/proteins mediating the β-cell survival and proliferative
effects of Ang(1-2) in human islets. The ability of angiotensin(1-2) to inhibit apoptosis, reduce
dedifferentiation and enhance proliferation of β cells will be examined in human islets under non-diabetic and
diabetic conditions. The contribution of mechanisms independent of GLP-1 or GPRC6A will be determined.
Effectors of angiotensin(1-2) action will be identified using non-biased phosphoproteomics, then loss-/gain-of-
function studies in islets will serve as a preliminary screen for effectors that could be targeted therapeutically.
Specific Aim 3. To determine whether Ang(1-2) improves human islet function/survival in vivo, and
whether hydrolysis of Ang(1-7) is required for its anti-diabetic effects. We will utilize a human islet
transplant model to determine the ability of angiotensin(1-2) to improve β-cell function/survival and glycemia in
diabetic mice. Further, we will test whether the insulinotropic action of angiotensin(1-7) requires its hydrolysis,
as is the case in vitro. The latter is highly significant for clinical management of T2D because it will inform on
the utility of hydrolysis-resistant angiotensin(1-7)-based medications currently in development.
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海外基金