Human iPSC Model to Elucidate Metabolic Interplay in Diabetic Cardimyopathy
人类 iPSC 模型阐明糖尿病心肌病代谢相互作用
基本信息
- 批准号:10732492
- 负责人:
- 金额:$ 69.63万
- 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:2019-04-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAblationAgeAnimal ModelBindingBinding ProteinsBlood PressureBlood VesselsCOVID-19 pandemicCRISPR/Cas technologyCalciumCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular ModelsCardiovascular systemCause of DeathCell LineCell physiologyCellsCirculationConditioned Culture MediaCoronaryCoronary ArteriosclerosisDevelopmentDiabetes MellitusDiabetic mouseEchocardiographyEndothelial CellsEpigenetic ProcessExcretory functionFibroblastsGenesGeneticGlucoseGrantHeartHeart DiseasesHigh Fat DietHistologyHumanHypertensionHypertrophyImageIn VitroJournalsKidneyLongevityMass Spectrum AnalysisMeasuresMetabolicMetabolic DiseasesMetabolic PathwayMitochondriaModalityModelingMolecularMutationMyocardialMyocardial dysfunctionNon-Insulin-Dependent Diabetes MellitusObesityPaperPathologyPathway interactionsPatientsPeptidesPhenotypePoint MutationProliferatingProteinsProteolysisProteomicsProtocols documentationPublicationsPublishingQiReportingResearchResolutionRespirationRoleSodiumSystems BiologyTherapeuticTissue HarvestingTissuesType 2 diabeticValidationcardiac tissue engineeringcardioprotectioncell typedesigndiabetes pathogenesisdiabeticdiabetic cardiomyopathydirected differentiationendothelial stem cellethnic diversitygenetic variantgenome sequencingglucose toleranceglucose uptakeheart functionin vitro Modelinduced pluripotent stem cellinduced pluripotent stem cell technologyinhibitormetabolic phenotypemetabolomicsmigrationmortalitymouse modelnovelnovel therapeuticspatient subsetssexsingle cell sequencingsingle-cell RNA sequencingstem cell modelstem cellssymporterwhole genome
项目摘要
Project Summary
Type 2 diabetes (T2D) is a leading cause of death nationwide with 65% of mortality due to cardiovascular
disease. The term “diabetic cardiomyopathy (T2DCM)” refers to a condition with adverse myocardial structural
changes, in the absence of hypertension and vascular pathology. Although T2D and CVD are tightly intertwined,
we lack a deeper understanding of T2DCM at the molecular and cellular levels. In recent years, sodium-glucose
cotransporter-2 (SGLT2) inhibitors have emerged as a promising therapeutic for T2DCM, but the precise
protective mechanisms in cardiomyocytes, fibroblasts, and endothelial cells which construct the cardiac
microenvironment remain incompletely understood. In this multi-PI R01 renewal, our team will elucidate the
mechanisms of metabolic interplay within and between cardiovascular cells which confer cardiac protection by
SGLT2 inhibition. We will harness induced pluripotent stem cell (iPSC) technology to generate diabetic models
of cardiovascular cell types for cellular and metabolic phenotyping of SGLT2 inhibition in vitro (Aim 1). We will
construct iPSC-derived engineered heart tissues for functional phenotyping and proteomic determination of the
SGLT2 inhibitor protein interactome (Aim 2). Afterward, we will validate cardioprotective mechanisms in a
diabetic mouse model at single-cell resolution (Aim 3). In summary, understanding the exact role and mechanism
of SGLT2 inhibition in T2DCM may contribute to finding new therapeutic modalities for the treatment of metabolic
heart diseases.
项目摘要
2型糖尿病(T2D)是全国范围内主要的死亡原因,65%的死亡是由心血管疾病引起的
疾病。术语“糖尿病心肌病(T2DCM)”是指一种心肌结构不良的疾病
变化,在没有高血压和血管病变的情况下。尽管T2D和CVD紧密交织在一起,
我们在分子和细胞水平上对T2DCM缺乏更深入的了解。近年来,葡萄糖钠
辅转运蛋白-2(SGLT2)抑制剂已经成为治疗T2 DCM的一种有前途的药物,但准确的
构成心脏的心肌细胞、成纤维细胞和内皮细胞的保护机制
对微环境的认识还不完全。在这次多PI R01更新中,我们的团队将阐明
心血管细胞内和心血管细胞间代谢相互作用的机制
SGLT2抑制作用。我们将利用诱导多能干细胞(IPSC)技术来建立糖尿病模型
体外抑制SGLT2的细胞和代谢表型的心血管细胞类型(目标1)。我们会
构建IPSC来源的工程化心脏组织用于功能表型和蛋白质组学测定
SGLT2抑制蛋白相互作用组(AIM 2)。之后,我们将验证心脏保护机制
单细胞分辨率糖尿病小鼠模型(目标3)。总而言之,了解其确切的作用和机制
抑制T2DCM中SGLT2的表达可能有助于寻找治疗代谢疾病的新方法
心脏病。
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)
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Ronglih Liao其他文献
Ronglih Liao的其他文献
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{{ truncateString('Ronglih Liao', 18)}}的其他基金
Modeling Cardiovascular Risks of Air Pollutants with Human Induced Pluripotent Stem Cell-Derived Cardiovascular-Associated Cells (Project 3) for the Air pollution disrupts Inflammasome Regulation in
使用人类诱导多能干细胞衍生的心血管相关细胞(项目 3)模拟空气污染物的心血管风险,以了解空气污染扰乱炎症体调节的情况
- 批准号:
10684174 - 财政年份:2021
- 资助金额:
$ 69.63万 - 项目类别:
Annual Symposium of the AHA Basic Cardiovascular Sciences Council, 2018 Scientific Sessions: Pathways to Cardiovascular Therapeutics
AHA 基础心血管科学委员会年度研讨会,2018 年科学会议:心血管治疗之路
- 批准号:
9613178 - 财政年份:2018
- 资助金额:
$ 69.63万 - 项目类别:
Mulan: a novel regulator of mitochondrial dynamics, mitophagy and heart function
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AHA Basic Cardiovascular Sciences Council (BCVS), 2017 Scientific Sessions: Pathways to Cardiovascular Therapeutics
AHA 基础心血管科学委员会 (BCVS),2017 年科学会议:心血管治疗之路
- 批准号:
9397896 - 财政年份:2017
- 资助金额:
$ 69.63万 - 项目类别:
Mulan: a novel regulator of mitochondrial dynamics, mitophagy and heart function
Mulan:线粒体动力学、线粒体自噬和心脏功能的新型调节剂
- 批准号:
9789492 - 财政年份:2017
- 资助金额:
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Metabolic underpinnings of AL amyloid cardiomyopathy
AL 淀粉样心肌病的代谢基础
- 批准号:
9034665 - 财政年份:2015
- 资助金额:
$ 69.63万 - 项目类别:
Metabolic underpinnings of AL amyloid cardiomyopathy
AL 淀粉样心肌病的代谢基础
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9207079 - 财政年份:2015
- 资助金额:
$ 69.63万 - 项目类别:
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Abcg2/Bcrp1 在心侧细胞群中的作用
- 批准号:
8080804 - 财政年份:2008
- 资助金额:
$ 69.63万 - 项目类别:
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8316406 - 财政年份:2008
- 资助金额:
$ 69.63万 - 项目类别:
Role of Abcg2/Bcrp1 in Cardiac Side Population Cells
Abcg2/Bcrp1 在心侧细胞群中的作用
- 批准号:
7663968 - 财政年份:2008
- 资助金额:
$ 69.63万 - 项目类别:
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