TP-R: a novel mediator of obesity-linked insulin resistance in humans
TP-R:人类肥胖相关胰岛素抵抗的新型介质
基本信息
- 批准号:10426085
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AbdomenAdipocytesAdipose tissueAffectAmidohydrolasesAmino AcidsAnti-Inflammatory AgentsArachidonic AcidsBindingBiochemicalBiologicalBody WeightBranched-Chain Amino AcidsCase-Control StudiesCatabolismCell LineCellsClinicalClinical InvestigatorClinical ResearchCollaborationsCorrelation StudiesDataDevelopmentDietEnzymesEssential Amino AcidsExposure toFatty AcidsFutureGeneral PopulationGenesGlucoseHemostatic functionHigh Fat DietHistidineHistidine Ammonia-LyaseHistidine Metabolism PathwayHumanHyperglycemiaIL8 geneIndividualInflammationInflammatoryInflammatory ResponseInsulinInsulin ResistanceLinkMeasuresMediatingMediator of activation proteinMetabolicMetabolic ControlMetabolic DiseasesMetabolic PathwayMetabolismMissionMolecularMorbid ObesityMusNon-Insulin-Dependent Diabetes MellitusObesityObesity associated diseaseOperative Surgical ProceduresOverweightPTEN genePathway interactionsPatientsPeripheral Blood Mononuclear CellPlasmaPlayProcessProstaglandinsProteinsProto-Oncogene Proteins c-aktReceptor ActivationReceptor GeneRegulationResearchRiskRisk FactorsRoleScientistSignal TransductionStimulusSupplementationTherapeuticThinnessThromboxane A2ThromboxanesTriglyceridesVeteransVisceralactivity markeramino acid metabolismblood glucose regulationdiet-induced obesityexperimental studyglucose metabolismglucose uptakeimprovedinflammatory markerinsulin sensitivityinsulin sensitizing drugsinsulin signalinglipid mediatormRNA Expressionmembermouse modelnovelnovel therapeutic interventionnovel therapeuticsobese patientsobese personobesity managementperipheral bloodpreclinical studyreceptorreceptor expressionsmall molecule inhibitorsubcutaneoustargeted treatmenttherapeutic targettranslational studyuptakevasoconstriction
项目摘要
Thromboxane A2 (TXA2), a pro-inflammatory lipid mediator derived from arachidonic acid, exerts
its biological effects via thromboxane-prostanoid receptor (TP-R). However, it is currently
unknown whether TP-R can modulate metabolic pathways. Although the adipocytes are mainly
involved in the storage of excess triglycerides, emerging evidence suggests that they have an
important role in amino acid (AA) metabolism, in particular branched chain AAs; of note, elevated
plasma levels of branched chain AAs is strongly associated with insulin resistance. However, the
role of adipose tissue (AT) in the metabolism of other essential AAs is still unclear. The preliminary
data provide evidence that mice lacking TP-R (TP-R-/- mice) grow lean when exposed to a high
caloric diet. Moreover, a striking increase in markers of histidine catabolism in the AT of TP-R-/-
mice was noted. Further, these mice showed a reduction in AT inflammation and improvement in
insulin sensitivity and glucose homeostasis on a high fat diet. Therefore, the overall hypothesis is
that TP-R plays an important role in mediating obesity-related inflammation and insulin
resistance via altered His and/or glucose metabolism in adipose tissue. Clinical,
biochemical, and molecular approaches will be employed to determine the potential of TP-R as a
therapeutic target in obesity-related insulin resistance and investigate the mechanisms by
which TP-R blockade improves insulin resistance, inflammation, and histidine and glucose
metabolism in AT. In Specific Aim 1, we will conduct studies subcutaneous and visceral AT and
PBMCs collected from lean/overweight insulin sensitive and obese insulin resistant subjects.
We will compare TP-R expression in AT and PBMCs between lean/overweight insulin
sensitive and obese insulin resistant subjects and determine the potential of TP-R as a target
for therapy against obesity-linked insulin resistance in humans. In addition, detailed
mechanistic studies will be conducted in cultured AT explants, primary adipocytes and
human adipocyte cell-line to determine mechanisms by which TP-R promotes insulin
resistance. In Specific Aim 2, we will correlate visceral and subcutaneous AT TP-R
expression with markers of inflammation. In addition, we will determine mechanisms by
which TP-R promotes inflammatory response in AT explants, adipocyte cell-line, and PBMCs.
In Specific Aim 3, we will correlate visceral and subcutaneous AT TP-R with histidine
transporters in AT, in particular Slc15a4. Furthermore, we will perform studies in cultured
explants and cells to determine the role and mechanism of TP-R in modulating histidine and/or
glucose metabolism. The findings will be relevant to uncover the role of TP-R in metabolic
control and develop novel therapeutic strategies to manage hyperglycemia in obesity and type
2 diabetes.
血栓素A2(TXA 2)是一种由花生四烯酸衍生的促炎脂质介质,
其生物学效应通过血栓素-前列腺素受体(TP-R)实现。但目前
目前尚不清楚TP-R是否能调节代谢途径。虽然脂肪细胞主要是
参与多余甘油三酯的储存,新出现的证据表明,他们有一个
在氨基酸(AA)代谢中起重要作用,特别是支链AA;值得注意的是,
支链AA的血浆水平与胰岛素抗性密切相关。但
脂肪组织(AT)在其它必需氨基酸代谢中的作用尚不清楚。初步
数据提供了证据表明,缺乏TP-R的小鼠(TP-R-/-小鼠)在暴露于高浓度时会变瘦。
高热量饮食此外,在TP-R-/-AT中组氨酸催化剂标记物的显著增加,
老鼠注意到。此外,这些小鼠表现出AT炎症的减少和
胰岛素敏感性和葡萄糖稳态。因此,总体假设是
TP-R在介导肥胖相关炎症和胰岛素分泌中起重要作用,
通过改变脂肪组织中的His和/或葡萄糖代谢来抵抗。临床,
生物化学和分子方法将被用来确定TP-R作为一种
肥胖相关胰岛素抵抗的治疗靶点,并通过
其中TP-R阻断改善胰岛素抵抗、炎症、组氨酸和葡萄糖
AT代谢在具体目标1中,我们将进行皮下和内脏AT研究,
从瘦/超重胰岛素敏感和肥胖胰岛素抵抗受试者收集PBMC。
我们将比较瘦/超重胰岛素组AT和PBMC中TP-R的表达,
敏感和肥胖的胰岛素抵抗受试者,并确定TP-R作为靶点的潜力
用于治疗人类肥胖相关的胰岛素抵抗。此外,详细
将在培养的AT外植体、原代脂肪细胞和
人脂肪细胞系测定TP-R促进胰岛素的机制
阻力在特定目标2中,我们将内脏和皮下AT TP-R
炎症标志物的表达。此外,我们将通过以下方式确定机制:
其中TP-R促进AT外植体、脂肪细胞系和PBMC中的炎症反应。
在具体目标3中,我们将内脏和皮下AT TP-R与组氨酸
AT中的转运蛋白,特别是Slc 15 a4。此外,我们将在培养的
外植体和细胞,以确定TP-R在调节组氨酸和/或
葡萄糖代谢这些发现将有助于揭示TP-R在代谢中的作用。
控制和开发新的治疗策略,以管理肥胖和肥胖型高血糖症
2糖尿病.
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 }}
Cyrus V Desouza其他文献
Racial differences in measures of glycemia in the Vitamin D and Type 2 Diabetes (D2d) Study: a secondary analysis of a randomized trial
维生素 D 和 2 型糖尿病 (D2d) 研究中血糖测量值的种族差异:随机试验的二次分析
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:4.1
- 作者:
Erin S LeBlanc;A. Pittas;Jason Nelson;Ranee Chatterjee;Neda Rasouli;M. Rhee;R. Pratley;Cyrus V Desouza;Lisa M Neff;Anne M Peters;Sam Dagogo;Daniel S. Hsia - 通讯作者:
Daniel S. Hsia
Cyrus V Desouza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('Cyrus V Desouza', 18)}}的其他基金
TP-R: a novel mediator of obesity-linked insulin resistance in humans
TP-R:人类肥胖相关胰岛素抵抗的新型介质
- 批准号:
10709488 - 财政年份:2021
- 资助金额:
-- - 项目类别:
相似国自然基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
- 批准号:81970721
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
- 批准号:
321208980 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8827438 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
- 批准号:
26450168 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
- 批准号:
257256526 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8828181 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8520690 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8629741 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
- 批准号:
23700778 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
- 批准号:
21780261 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
- 批准号:
7610781 - 财政年份:2007
- 资助金额:
-- - 项目类别: