Wnt signaling control of vascular phenotype in obesity
Wnt 信号控制肥胖血管表型
基本信息
- 批准号:10221037
- 负责人:
- 金额:$ 63.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-16 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAdipose tissueAgeAmericanAreaBariatricsBiologicalBiological AssayBiologyBiopsyBlood VesselsBody Weight decreasedCardiovascular DiseasesCardiovascular systemCause of DeathCellsChronic DiseaseClinicalDataDiseaseElective Surgical ProceduresEndothelial CellsEndotheliumEngineeringFunctional disorderGenderGenetic ModelsHealthcareHeart DiseasesHumanInflammationInflammatoryInsulin ResistanceIntra-abdominalInvestigationLeadLifeLinkMediatingMediator of activation proteinMedicalMesenchymalMetabolicMetabolic DiseasesMethodsMolecularMorbid ObesityMusMyeloid CellsNitric OxideObesityOperative Surgical ProceduresOverweightPathogenesisPathogenicityPathway interactionsPatientsPharmacologyPhenotypePhysiologyPlayPopulationProcessPublic HealthPublishingReagentRegulationRoleSavingsScientistSignal PathwaySignal TransductionSpecimenStrokeTestingTherapeuticThinnessTissuesTransforming Growth Factor betaUnited States National Institutes of HealthUp-RegulationVascular DiseasesVasodilator AgentsVasomotorVideo MicroscopyVisceralVisceral fatWNT Signaling PathwayWNT5A geneWorkarteriolebariatric surgerybasecardiometabolic riskcardiovascular risk factorclinically relevantcombatendothelial dysfunctionhuman tissueimprovedinhibitor/antagonistinterdisciplinary approachinterestmetabolic phenotypemortalitymouse geneticsmouse modelmultidisciplinarynovelobese personoverexpressionpatient orientedplanar cell polarityresponsesubcutaneoustherapeutic targetvascular endothelial dysfunctionweight loss intervention
项目摘要
Project Summary/Abstract
The current proposal represents a combined clinical patient-oriented and experimental murine
investigation which seeks to examine mechanisms of vascular dysfunction in obesity. Obesity has
developed into one of our most critical health care problems as 69% of the US population is currently
overweight or obese. Adipose tissue dysfunction, inflammation, and insulin resistance are essential
hallmarks linking obesity to the pathogenesis of cardiovascular disease. Our preliminary data
demonstrate marked up-regulation of a unique pro-inflammatory Wnt signaling pathway that may play a
major role in mechanisms of vascular dysfunction in obesity. In this proposal, we will examine the role
of Wnt signaling in the regulation of microvascular endothelial function in intact blood vessels and
isolated endothelial cells acquired from living subjects. We will utilize a multidisciplinary approach and
complementary expertise between clinical and basic scientists to characterize the pathophysiological
role of dysfunctional Wnt5a signaling. In aim 1, we will characterize depot-specific mechanisms of
vascular endothelial dysfunction in human adipose tissue arterioles using videomicroscopy of small
vessels isolated from subcutaneous and visceral fat compartments during elective surgical procedures
in 150 obese and 50 age- and gender-matched lean subjects. We will characterize vascular
phenotypes in relation to Wnt signaling and test the hypothesis that over-activation of Wnt5a-mediated
signaling is a dominant regulatory feature that leads to vascular dysfunction. In aims 2 and 3, specific
pharmacological and biological inhibitors of the Wnt5a and TGFβ pathways will be employed using
arterioles and endothelial cells from aim 1 to test the hypothesis that antagonism of Wnt5a reverses
vascular dysfunction, in part through its ability to modulate EndoMT in adipose tissue, and seek to
identify novel regulators and therapeutic targets in obesity. To corroborate these findings in genetic
models, we will explore EndoMT and the vascular and metabolic phenotypes of mice that are
engineered to conditionally ablate or overexpress Wnt5a in myeloid cells. In aim 4, studies of
endothelial phenotyping will be repeated 6-months after life-saving bariatric weight loss surgical
intervention in the same 150 obese subjects from aim 1 to examine the effects of marked weight
reduction on arteriolar responses and relevant Wnt molecular pathways identified in aims 2 and 3. The
overall project combines studies of cellular signaling and whole vessel physiology using primary tissues
from severely obese individuals where clinically very little vascular data currently exist. Our proposal
may identify the Wnt5a-Sfrp5 axis as a novel modulator of vascular biology and potentially lead to the
identification of new targets and approaches to combat obesity-induced cardiovascular disease.
项目总结/摘要
目前的建议代表了一个结合临床病人为导向和实验鼠
该研究旨在研究肥胖症中血管功能障碍的机制。肥胖已
发展成为我们最关键的医疗保健问题之一,因为69%的美国人口目前
超重或肥胖。脂肪组织功能障碍、炎症和胰岛素抵抗是必不可少的
肥胖与心血管疾病发病机制的联系。我们的初步数据
证明了一种独特的促炎Wnt信号通路的显著上调,
在肥胖症血管功能障碍机制中的重要作用。在本提案中,我们将研究
Wnt信号在完整血管微血管内皮功能调节中的作用,
从活体中获得的分离的内皮细胞。我们将采用多学科方法,
临床和基础科学家之间的互补专业知识,以表征病理生理学
功能失调的Wnt 5a信号传导的作用。在目标1中,我们将描述
应用小血管显微镜观察人脂肪组织小动脉血管内皮功能障碍
在择期外科手术期间从皮下和内脏脂肪隔室分离的血管
在150名肥胖者和50名年龄和性别匹配的瘦受试者中。我们将描述血管
表型相关的Wnt信号和测试的假设,过度激活Wnt 5a介导的
信号传导是导致血管功能障碍的主要调节特征。在目标2和3中,具体
将使用Wnt 5a和TGFβ途径的药理学和生物学抑制剂,
目的1中的小动脉和内皮细胞,以检验Wnt 5a的拮抗作用逆转
血管功能障碍,部分通过其调节脂肪组织中EndoMT的能力,并寻求
确定肥胖症中新的调节剂和治疗靶点。为了证实这些发现,
模型,我们将探讨EndoMT和血管和代谢表型的小鼠,
工程化以在骨髓细胞中有条件地消除或过表达Wnt 5a。在目标4中,
在挽救生命的减肥手术后6个月将重复内皮表型分析
对目标1中相同的150名肥胖受试者进行干预,
目的2和3中鉴定的小动脉反应和相关Wnt分子途径的减少。的
整个项目结合了细胞信号和使用原代组织的整个血管生理学的研究
来自目前临床上几乎没有血管数据的严重肥胖个体。我们的建议
可能将Wnt 5a-Sfrp 5轴确定为血管生物学的新调节剂,并可能导致血管内皮细胞的凋亡。
确定防治肥胖引起的心血管疾病的新目标和方法。
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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NOYAN GOKCE其他文献
NOYAN GOKCE的其他文献
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{{ truncateString('NOYAN GOKCE', 18)}}的其他基金
Impact of Per/Polyfluoroalkyl pollutants on vascular disease mechanisms
全氟烷基/多氟烷基污染物对血管疾病机制的影响
- 批准号:
10751239 - 财政年份:2023
- 资助金额:
$ 63.65万 - 项目类别:
Wnt signaling control of vascular phenotype in obesity
Wnt 信号控制肥胖血管表型
- 批准号:
10666496 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
Wnt signaling control of vascular phenotype in obesity
Wnt 信号控制肥胖血管表型
- 批准号:
10458520 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
Wnt signaling control of vascular phenotype in obesity
Wnt 信号控制肥胖血管表型
- 批准号:
9816682 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
Identifying a novel regulatory pathway of vascular function in obesity
确定肥胖症血管功能的新调节途径
- 批准号:
10171887 - 财政年份:2018
- 资助金额:
$ 63.65万 - 项目类别:
Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity
脂肪炎症、线粒体功能
- 批准号:
8505531 - 财政年份:2012
- 资助金额:
$ 63.65万 - 项目类别:
Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity
脂肪炎症、线粒体功能
- 批准号:
9105611 - 财政年份:2012
- 资助金额:
$ 63.65万 - 项目类别:
Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity
脂肪炎症、线粒体功能
- 批准号:
8340493 - 财政年份:2012
- 资助金额:
$ 63.65万 - 项目类别:
Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity
脂肪炎症、线粒体功能
- 批准号:
8689153 - 财政年份:2012
- 资助金额:
$ 63.65万 - 项目类别:
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