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.
项目摘要/摘要
目前的方案代表了临床以患者为中心和实验小鼠相结合的方案
一项旨在研究肥胖患者血管功能障碍机制的研究。肥胖症有
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。
将肥胖与心血管疾病的发病机制联系起来的特征。我们的初步数据
证明一种独特的促炎Wnt信号通路显著上调,该信号通路可能在
在肥胖症的血管功能障碍机制中起主要作用。在这份提案中,我们将研究
Wnt信号在完整血管微血管内皮细胞功能调节中的作用
从活体受试者获取的分离内皮细胞。我们将利用多学科方法,
临床和基础科学家之间的互补专业知识,以确定病理生理学特征
功能失调的Wnt5a信号转导系统的作用。在目标1中,我们将描述特定于仓库的机制
人脂肪组织小动脉血管内皮细胞功能障碍的电视显微镜观察
择期手术中从皮下和内脏脂肪隔间分离的血管
在150名肥胖者和50名年龄和性别匹配的瘦身受试者中。我们将描述血管的特征
表型与Wnt信号的关系,并验证Wnt5a过度激活介导的假说
信号是导致血管功能障碍的主要调节特征。在目标2和目标3中,具体
WNT5a和转化生长因子β途径的药理和生物抑制剂将用于
来自Aim 1的小动脉和内皮细胞,以检验WNT5a拮抗作用逆转的假设
血管功能障碍,部分是通过调节脂肪组织中的内源性MT的能力,并寻求
确定肥胖症的新调节剂和治疗靶点。以证实这些发现在遗传学上
模型,我们将探索EndoMT以及小鼠的血管和代谢表型
被设计成有条件地去除或在髓系细胞中过度表达WNT5a。在目标4中,研究
救命减肥手术后6个月内皮细胞表型将重复
从目标1开始对相同的150名肥胖受试者进行干预,以检查标记体重的影响
AIMS 2和3中发现的小动脉反应和相关的Wnt分子通路的减少。
整个项目结合了细胞信号和使用初级组织的全血管生理学的研究
来自严重肥胖的人,目前临床上几乎没有血管数据。我们的建议
可能确定Wnt5a-Sfrp5轴是一种新的血管生物学调节器,并可能导致
确定抗击肥胖引起的心血管疾病的新目标和新方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
NOYAN GOKCE其他文献
NOYAN GOKCE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
8689153 - 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:
相似海外基金
Examination of factors associated with trunk intramuscular adipose tissue content : Aspects of sex, age, and racial differences
躯干肌内脂肪组织含量相关因素的检查:性别、年龄和种族差异
- 批准号:
23KJ1130 - 财政年份:2023
- 资助金额:
$ 63.65万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Does age-dependent PFKFB3 down-regulation alter adipose tissue function
年龄依赖性 PFKFB3 下调是否会改变脂肪组织功能
- 批准号:
10563615 - 财政年份:2022
- 资助金额:
$ 63.65万 - 项目类别:
Dietary Protein Restriction Remodels Adipose Tissue to Defend Against Age-Related Metabolic Decline
饮食蛋白质限制重塑脂肪组织以防御与年龄相关的代谢下降
- 批准号:
10828031 - 财政年份:2021
- 资助金额:
$ 63.65万 - 项目类别:
Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment
针对年龄相关血管认知障碍的脂肪组织生热作用
- 批准号:
10490299 - 财政年份:2021
- 资助金额:
$ 63.65万 - 项目类别:
Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment
针对年龄相关血管认知障碍的脂肪组织生热作用
- 批准号:
10674854 - 财政年份:2021
- 资助金额:
$ 63.65万 - 项目类别:
Dietary Protein Restriction Remodels Adipose Tissue to Defend Against Age-Related Metabolic Decline
饮食蛋白质限制重塑脂肪组织以防御与年龄相关的代谢下降
- 批准号:
10302155 - 财政年份:2021
- 资助金额:
$ 63.65万 - 项目类别:
Dietary Protein Restriction Remodels Adipose Tissue to Defend Against Age-Related Metabolic Decline
饮食蛋白质限制重塑脂肪组织以防御与年龄相关的代谢下降
- 批准号:
10478936 - 财政年份:2021
- 资助金额:
$ 63.65万 - 项目类别:
Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment
针对年龄相关血管认知障碍的脂肪组织生热作用
- 批准号:
10283749 - 财政年份:2021
- 资助金额:
$ 63.65万 - 项目类别:
Analysis of physiological roles of FABP5 in age-related chronic inflammation in adipose tissue
FABP5在脂肪组织年龄相关慢性炎症中的生理作用分析
- 批准号:
19K20172 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The pathological role of brown adipose tissue dysfunction in age related disorders.
棕色脂肪组织功能障碍在年龄相关疾病中的病理作用。
- 批准号:
26893080 - 财政年份:2014
- 资助金额:
$ 63.65万 - 项目类别:
Grant-in-Aid for Research Activity Start-up