Profiling extracellular vesicle cargo in obesity and type 2 diabetes
分析肥胖和 2 型糖尿病中的细胞外囊泡货物
基本信息
- 批准号:10018896
- 负责人:
- 金额:$ 72.24万
- 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:2019-09-20 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAgeAnalysis of VarianceBiological AssayBody Weight decreasedCell CommunicationCellsChronicClassificationDevelopmentDiabetes MellitusDisease remissionEthnic OriginGenetic TranscriptionGlucose IntoleranceHumanITGAM geneIndividualInflammationInflammatoryInsulin ResistanceInvestigationKnowledgeLeadLinkLipidsMass Spectrum AnalysisMeasuresMediatingMediator of activation proteinMembraneMessenger RNAMetabolicMicroRNAsMiningModelingMolecularMorbid ObesityMusNon-Insulin-Dependent Diabetes MellitusNucleic AcidsObese MiceObesityOperative Surgical ProceduresPathogenesisPatientsPatternPlasmaPlayProteinsProteomicsPublishingRNAReverse Transcriptase Polymerase Chain ReactionRiskRisk FactorsRoleSample SizeSamplingSampling StudiesShotgunsSourceThinnessTissue SampleTissuesTranscriptValidationVesicleVisceralWorkadipokinesbariatric surgerycell typecellular targetingcohortdiabeticdrug developmentexperienceextracellular vesiclesfatty acid-binding proteinsglucose metabolismglucose toleranceglycemic controlimprovedmacrophagemembernew therapeutic targetprotein expressionrestorationsex
项目摘要
PROJECT SUMMARY/ABSTRACT
Obesity
diabetes
adipose
spectrum
Emerging
is linked with heightened risk of insulin resistance and type 2
(T2D) Obesity is also associated attributed primarily to visceral
tissue (VAT), which increases T2D risk; however, the precise molecular mechanisms underlying the
inflammatory and metabolic mediators of dysglycemia in obesity remain poorly
studies support a role for extracellular vesicles (EVs) in both T2D and obesity.
metabolic
abnormalities,
including
. with chronic low-grade inflammation,
of understood.
EVs are a
heterogeneous class of membrane vesicles that participate in cell-cell communication through exchange of
proteins, lipids, and nucleic acids. Circulating and adipocyte-derived EVs have been shown to increase in
obesity, decrease following weight reduction, and correlate with restoration of glycemic control in T2D patients
following bariatric surgery. Adipose-derived EVs may also mediate T2D pathogenesis. We hypothesize that
protein and RNA cargo of circulating EVs contribute to metabolic derangements in obesity, and
correspondingly, to improvements in glucose metabolism associated with bariatric surgery. To address this
hypothesis, we propose a strategy to identify EV-derived protein and RNA profiles associated with obesity-
related T2D. In Aim 1, we will
derived
transcripts
assess protein and RNA (lncRNA, miRNA, and mRNA) content in plasma-
EVs obtained from T2D (N=60) and normoglycemic (N=60) individuals with obesity. Proteins and
showing T2D-associated patterns will be analyzed in an independent study sample (N=120).
Completion of this aim will result in the identification and validation of protein and RNA profiles associated with
T2D in extreme obesity. In Aim 2, we propose to determine whether T2D-associated protein and RNA
signatures emanate from VAT by evaluating cargo (protein and RNA) isolated from immuno-selected fractions
of EVs and from EVs obtained from VAT-conditioned media. Determining
involved we will establish
whether T2D-associated signatures are lost in patients who experience T2D remission following bariatric
surgery, but retained in those who remain diabetic, even in the presence of significant weight loss. In specific,
we will measure T2D-associated protein and RNA profiles identified and validated in Aim 1 in individuals who
whether VAT is the
in the pathogenesis of T2D will provide a cellular target for further studies. In Aim 3,
source
of
EVs
experience T2D remission and those who remain diabetic. Completion of this
understanding The combination of
plasma and VAT samples from bariatric surgery patients and state-of-the-art molecular characterization
provides a unique opportunity to identify those patients likely to receive the greatest benefit from bariatric
surgery, improve our understanding of T2D pathogenesis, and perhaps lead to the development of drugs that
mimic effects of surgery.
of
the
mechanisms
underlying
T2D
remission
following
aim is expected to enhance our
bariatric surgery.
项目概要/摘要
肥胖
糖尿病
脂肪
光谱
新兴
与胰岛素抵抗和 2 型胰岛素抵抗风险增加有关
(T2D) 肥胖也主要归因于内脏
组织(增值税),这会增加 T2D 风险;然而,其背后的精确分子机制
肥胖者血糖异常的炎症和代谢介质仍然很差
研究支持细胞外囊泡 (EV) 在 T2D 和肥胖症中的作用。
新陈代谢的
异常,
包括
。患有慢性低度炎症,
的理解。
电动汽车是
通过交换参与细胞间通讯的异质类膜囊泡
蛋白质、脂质和核酸。循环和脂肪细胞衍生的 EV 已被证明会增加
肥胖、体重减轻后减少以及与 T2D 患者血糖控制恢复相关
减肥手术后。脂肪来源的 EV 也可能介导 T2D 发病机制。我们假设
循环 EV 的蛋白质和 RNA 货物会导致肥胖的代谢紊乱,以及
相应地,与减肥手术相关的葡萄糖代谢的改善。为了解决这个问题
假设,我们提出了一种策略来识别与肥胖相关的 EV 衍生蛋白和 RNA 谱 -
相关 T2D。在目标 1 中,我们将
衍生的
成绩单
评估血浆中的蛋白质和 RNA(lncRNA、miRNA 和 mRNA)含量
从 T2D (N=60) 和血糖正常 (N=60) 肥胖个体获得的 EV。蛋白质和
显示 T2D 相关模式将在独立研究样本 (N=120) 中进行分析。
完成这一目标将导致与相关的蛋白质和 RNA 图谱的鉴定和验证
极度肥胖的 T2D。在目标 2 中,我们建议确定 T2D 相关蛋白和 RNA 是否
通过评估从免疫选择组分中分离出的货物(蛋白质和 RNA),从 VAT 中产生特征
的电动汽车和从增值税条件媒体获得的电动汽车。确定
我们将参与其中
减肥后 T2D 缓解的患者中 T2D 相关特征是否会丢失
手术,但保留在那些仍然患有糖尿病的人身上,即使体重明显减轻。具体来说,
我们将测量目标 1 中确定和验证的 T2D 相关蛋白和 RNA 谱:
是否增值税
T2D 发病机制中的作用将为进一步研究提供细胞靶点。在目标 3 中,
来源
的
电动汽车
经历 T2D 缓解的人和仍然患有糖尿病的人。完成此
理解 的组合
来自减肥手术患者的血浆和 VAT 样本以及最先进的分子表征
提供了一个独特的机会来识别那些可能从减肥治疗中获得最大益处的患者
手术,提高我们对 T2D 发病机制的了解,并可能导致药物的开发
模拟手术的效果。
的
这
机制
潜在的
T2D
缓解
下列的
预计目标是增强我们的
减肥手术。
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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Johanna K DiStefano其他文献
Johanna K DiStefano的其他文献
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{{ truncateString('Johanna K DiStefano', 18)}}的其他基金
Extracellular vesicle cargo and risk of NAFLD and NASH in Latino youth
拉丁裔青年的细胞外囊泡负载以及 NAFLD 和 NASH 的风险
- 批准号:
10446517 - 财政年份:2022
- 资助金额:
$ 72.24万 - 项目类别:
Extracellular vesicle cargo and risk of NAFLD and NASH in Latino youth
拉丁裔青年的细胞外囊泡负载以及 NAFLD 和 NASH 的风险
- 批准号:
10609057 - 财政年份:2022
- 资助金额:
$ 72.24万 - 项目类别:
Profiling extracellular vesicle cargo in obesity and type 2 diabetes
分析肥胖和 2 型糖尿病中的细胞外囊泡货物
- 批准号:
10684629 - 财政年份:2019
- 资助金额:
$ 72.24万 - 项目类别:
Profiling extracellular vesicle cargo in obesity and type 2 diabetes
分析肥胖和 2 型糖尿病中的细胞外囊泡货物
- 批准号:
10234093 - 财政年份:2019
- 资助金额:
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Epigenetic markers of severity in nonalcoholic fatty liver disease
非酒精性脂肪肝疾病严重程度的表观遗传标记
- 批准号:
9165134 - 财政年份:2016
- 资助金额:
$ 72.24万 - 项目类别:
Epigenetic markers of severity in nonalcoholic fatty liver disease
非酒精性脂肪肝疾病严重程度的表观遗传标记
- 批准号:
9356500 - 财政年份:2016
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$ 72.24万 - 项目类别:
Genetic determinants of NAFLD severity and progression
NAFLD 严重程度和进展的遗传决定因素
- 批准号:
8473212 - 财政年份:2011
- 资助金额:
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Genetic determinants of NAFLD severity and progression
NAFLD 严重程度和进展的遗传决定因素
- 批准号:
8712478 - 财政年份:2011
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Genetic determinants of NAFLD severity and progression
NAFLD 严重程度和进展的遗传决定因素
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Genetic determinants of NAFLD severity and progression
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- 批准号:
8087303 - 财政年份:2011
- 资助金额:
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