Role of Endothelial Regulation of Fatty Acid Uptake in Metabolic Dysfunction
内皮调节脂肪酸摄取在代谢功能障碍中的作用
基本信息
- 批准号:10222759
- 负责人:
- 金额:$ 52.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:APLN geneAddressAdultAffectAgonistAmericanAntidiabetic DrugsAtherosclerosisBlood VesselsCardiovascular DiseasesCardiovascular systemCessation of lifeClinicalComplications of Diabetes MellitusDataDiabetes MellitusDiseaseEmbryoEndotheliumEpidemicExperimental Diabetes MellitusFABP4 geneFOXO1A geneFatty AcidsG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGatekeepingGenesGlucoseHalf-LifeHealthcare SystemsHeart RateImpairmentIn VitroInsulinInsulin ReceptorInsulin ResistanceKnockout MiceKnowledgeLigandsMediatingMetabolicMetabolic dysfunctionModelingMusMyocardial InfarctionNon-Insulin-Dependent Diabetes MellitusOrganOutcomePathway interactionsPeptidesPharmaceutical PreparationsPharmacologyPhosphorylationReceptor SignalingRegulationResourcesRoleSignal PathwaySignal TransductionSkeletal MuscleStrokeTherapeuticTimeTranslatingatheroprotectivebasecardiovascular risk factorefficacy testingenhancer-binding protein AP-2fatty acid transportglycemic controlin vivoinhibitor/antagonistinnovationinsulin sensitivityinsulin signalingmetabolic phenotypenew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspatient populationprotective effectreceptorresistance mechanismresponsetherapeutic targettranscription factortrenduptake
项目摘要
Abstract
Cardiovascular complications of diabetes continue to remain a huge burden on the health care system. Of all
the currently approved anti-diabetic therapies, only one class to date has demonstrated any significant
improvement in cardiovascular outcomes. Novel therapeutic strategies that can couple improvements in
glycemic control with reduction of cardiovascular complications would represent a significant advancement in
how we manage these challenging patient population. To this end, we propose to investigate an exciting novel
strategy to target the endothelial based signaling cascade driven by the G protein coupled receptor APLNR, as
we characterize the mechanistic basis of its anti-glycemic and atheroprotective effects. A key mechanistic basis
for this strategy, as outlined in this proposal, is to exploit its function as the metabolic transport barrier that
actively regulates the transport and uptake of fatty acid in target organs such as skeletal muscles, which in turn
determines insulin sensitivity and glucose utilization. Our exciting preliminary data, including: : 1) demonstration
of marked impairment of glycemic control in conditional, endothelial specific Aplnr deleted mice, 2) discovery of
FOXO1, a key metabolic transcription factor, as a novel signaling target of apelin, whereby apelin induces its
inactivation via phosphorylation and cytoplasmic translocation, 3) demonstration that the negative regulation of
FOXO1 by apelin in the endothelium leads to suppression of FABP4 (AP2) expression, which regulates trans-
endothelial FA transport, and 4) identification of novel endothelial based crosstalk between apelin/APLNR and
insulin/insulin receptor (IR) signaling. Based on these provocative preliminary data, we will address the
hypothesis that endothelial APLNR signaling is an essential regulator of the endothelial function as a gatekeeper
of FA uptake and transport. Aim 1 will utilize in vivo and in vitro approaches to determine the mechanism of
crosstalk between apelin-APLNR signaling and insulin-IR signaling. Aim 2 will determine the metabolic role of
elabela, the recently identified second APLNR ligand. Aim 3 will push forward the translational application of
these findings by testing the efficacy and mechanistic basis of novel APLNR agonists in experimental diabetes
and atherosclerosis models. Overall, our studies will significantly expand our knowledge of a novel endothelial-
based signaling paradigm that regulates energy resource utilization, with multiple implications in the context of
the worldwide epidemic of diabetes and its associated cardiovascular complications.
摘要
糖尿病的心血管并发症仍然是卫生保健系统的巨大负担。所有
目前批准的抗糖尿病治疗,迄今为止只有一类已证明任何显着
改善心血管结局。新的治疗策略,可以结合改善
降低心血管并发症的血糖控制将代表着
我们如何管理这些具有挑战性的患者群体。为此,我们建议调查一部令人兴奋的小说,
靶向由G蛋白偶联受体APLNR驱动的基于内皮的信号级联的策略,
我们描述了其抗血糖和动脉粥样硬化保护作用的机制基础。一个关键的机械基础
对于这个策略,正如在这个提议中所概述的,是利用它作为代谢转运屏障的功能,
积极调节脂肪酸在靶器官如骨骼肌中的转运和摄取,
确定胰岛素敏感性和葡萄糖利用率。我们令人兴奋的初步数据,包括:1)演示
在有条件的内皮特异性Aplnr缺失小鼠中血糖控制的显著损害,2)发现
FOXO 1是一种重要的代谢转录因子,是爱帕琳的一个新的信号转导靶点,爱帕琳通过FOXO 1诱导其表达。
通过磷酸化和胞质易位失活,3)证明了
FOXO 1通过apelin在内皮中导致FABP 4(AP 2)表达的抑制,FABP 4(AP 2)表达调节反式-
内皮FA转运,和4)鉴定爱帕琳/APLNR和APLNR之间的新的基于内皮的串扰,
胰岛素/胰岛素受体(IR)信号传导。根据这些挑衅性的初步数据,我们将解决
假设内皮APLNR信号转导是内皮功能的重要调节因子,
FA的摄取和运输。目的1将利用体内和体外方法来确定
爱帕琳-APLNR信号传导和胰岛素-IR信号传导之间的串扰。目标2将确定代谢的作用,
最近发现的第二个APLNR配体。目标3将推动
这些发现是通过测试新的APLNR激动剂在实验性糖尿病中的功效和机制基础来实现的。
和动脉粥样硬化模型。总的来说,我们的研究将大大扩展我们对一种新的内皮细胞的认识,
基于信令范式,调节能源利用,在上下文中有多种含义,
糖尿病及其相关的心血管并发症的全球流行。
项目成果
期刊论文数量(6)
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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- DOI:10.1371/journal.pbio.3001373
- 发表时间:2021-08
- 期刊:
- 影响因子:9.8
- 作者:Wang SY;Takahashi T;Pine AB;Damsky WE;Simonov M;Zhang Y;Kieras E;Price CC;King BA;Siegel MD;Desir GV;Lee AI;Iwasaki A;Chun HJ
- 通讯作者:Chun HJ
Endothelial β-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia.
- DOI:10.1002/pul2.12167
- 发表时间:2022-10
- 期刊:
- 影响因子:2.6
- 作者:Park, Saejeong;Ma, Zhiyuan;Zarkada, Georgia;Papangeli, Irinna;Paluri, Sarin;Nazo, Nour;Rivera-Molina, Felix;Toomre, Derek;Rajagopal, Sudarshan;Chun, Hyung J.
- 通讯作者:Chun, Hyung J.
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Hyung Joon Chun其他文献
Hyung Joon Chun的其他文献
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{{ truncateString('Hyung Joon Chun', 18)}}的其他基金
Molecular Mechanisms of Neonatal Pulmonary Hemorrhage
新生儿肺出血的分子机制
- 批准号:
9565805 - 财政年份:2017
- 资助金额:
$ 52.86万 - 项目类别:
Role of MicroRNAs 424 and 503 in Pulmonary Arterial Hypertension
MicroRNA 424 和 503 在肺动脉高压中的作用
- 批准号:
8889297 - 财政年份:2012
- 资助金额:
$ 52.86万 - 项目类别:
Role of MicroRNAs 424 and 503 in Pulmonary Arterial Hypertension
MicroRNA 424 和 503 在肺动脉高压中的作用
- 批准号:
8397188 - 财政年份:2012
- 资助金额:
$ 52.86万 - 项目类别:
Role of MicroRNAs 424 and 503 in Pulmonary Arterial Hypertension
MicroRNA 424 和 503 在肺动脉高压中的作用
- 批准号:
9102161 - 财政年份:2012
- 资助金额:
$ 52.86万 - 项目类别:
Role of MicroRNAs 424 and 503 in Pulmonary Arterial Hypertension
MicroRNA 424 和 503 在肺动脉高压中的作用
- 批准号:
8534272 - 财政年份:2012
- 资助金额:
$ 52.86万 - 项目类别:
Role of MicroRNAs 424 and 503 in Pulmonary Arterial Hypertension
MicroRNA 424 和 503 在肺动脉高压中的作用
- 批准号:
8690959 - 财政年份:2012
- 资助金额:
$ 52.86万 - 项目类别:
Role of Apelin in the Systemic and Pulmonary Vasculature
Apelin 在全身和肺血管中的作用
- 批准号:
8131070 - 财政年份:2009
- 资助金额:
$ 52.86万 - 项目类别:
Role of Apelin in the Systemic and Pulmonary Vasculature
Apelin 在全身和肺血管中的作用
- 批准号:
7739643 - 财政年份:2009
- 资助金额:
$ 52.86万 - 项目类别:
Role of Apelin in the Systemic and Pulmonary Vasculature
Apelin 在全身和肺血管中的作用
- 批准号:
8267039 - 财政年份:2009
- 资助金额:
$ 52.86万 - 项目类别:
Role of Apelin in the Systemic and Pulmonary Vasculature
Apelin 在全身和肺血管中的作用
- 批准号:
7920245 - 财政年份:2009
- 资助金额:
$ 52.86万 - 项目类别:
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