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(T2 D)是全国死亡的主要原因,65%的死亡率是由于心血管疾病引起的。
疾病术语“糖尿病性心肌病(T2 DCM)”是指具有不利的心肌结构性损害的病症。
变化,在没有高血压和血管病理。虽然T2 D和CVD紧密交织在一起,
我们缺乏对T2 DCM在分子和细胞水平上的更深入了解。近年来,钠-葡萄糖
协同转运蛋白-2(SGLT 2)抑制剂已成为T2 DCM的有希望的治疗药物,但其精确的靶向作用可能是一种潜在的靶向治疗方法。
心肌细胞、成纤维细胞和内皮细胞的保护机制,
微环境仍然不完全了解。在本次多PI R 01更新中,我们的团队将阐明
心血管细胞内和之间的代谢相互作用机制,通过以下方式提供心脏保护:
SGLT 2抑制。我们将利用诱导多能干细胞(iPSC)技术来产生糖尿病模型
用于体外SGLT 2抑制的细胞和代谢表型分析(目的1)。我们将
构建iPSC衍生的工程化心脏组织,用于功能表型分析和蛋白质组学测定。
SGLT 2抑制蛋白相互作用体(Aim 2)。之后,我们将验证心脏保护机制,
糖尿病小鼠模型在单细胞分辨率(目标3)。总之,了解确切的作用和机制
在T2 DCM中SGLT 2抑制可能有助于寻找新的治疗方法来治疗代谢性
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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- 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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- 批准号:
9397896 - 财政年份:2017
- 资助金额:
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Mulan: a novel regulator of mitochondrial dynamics, mitophagy and heart function
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- 批准号:
9789492 - 财政年份:2017
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Metabolic underpinnings of AL amyloid cardiomyopathy
AL 淀粉样心肌病的代谢基础
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$ 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
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- 资助金额:
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