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

• 批准号: 10732492
• 负责人: Ronglih Liao
• 金额: $ 69.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10732492
• 关键词: 3-Dimensional; Ablation; Age; Animal Model; Binding; Binding Proteins; Blood Pressure; Blood Vessels; COVID-19 pandemic; CRISPR/Cas technology; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cause of Death; Cell Line; Cell physiology; Cells; Circulation; Conditioned Culture Media; Coronary; Coronary Arteriosclerosis; Development; Diabetes Mellitus; Diabetic mouse; Echocardiography; Endothelial Cells; Epigenetic Process; Excretory function; Fibroblasts; Genes; Genetic; Glucose; Grant; Heart; Heart Diseases; High Fat Diet; Histology; Human; Hypertension; Hypertrophy; Image; In Vitro; Journals; Kidney; Longevity; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Mitochondria; Modality; Modeling; Molecular; Mutation; Myocardial; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Paper; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Point Mutation; Proliferating; Proteins; Proteolysis; Proteomics; Protocols documentation; Publications; Publishing; Qi; Reporting; Research; Resolution; Respiration; Role; Sodium; Systems Biology; Therapeutic; Tissue Harvesting; Tissues; Type 2 diabetic; Validation; cardiac tissue engineering; cardioprotection; cell type; design; diabetes pathogenesis; diabetic; diabetic cardiomyopathy; directed differentiation; endothelial stem cell; ethnic diversity; genetic variant; genome sequencing; glucose tolerance; glucose uptake; heart function; in vitro Model; induced pluripotent stem cell; induced pluripotent stem cell technology; inhibitor; metabolic phenotype; metabolomics; migration; mortality; mouse model; novel; novel therapeutics; patient subsets; sex; single cell sequencing; single-cell RNA sequencing; stem cell model; stem cells; symporter; whole genome

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。