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：
Ronglih Liao
金额：
$ 69.63万
依托单位：
STANFORD UNIVERSITY
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：
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

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.

项目概要 2 型糖尿病 (T2D) 是全国范围内的首要死因，其中 65% 的死亡率是由心血管疾病引起的术语“糖尿病心肌病（T2DCM）”是指心肌结构不良的病症。尽管 T2D 和 CVD 紧密相连，但在没有高血压和血管病理的情况下，近年来，我们对T2DCM缺乏在分子和细胞水平上更深入的了解。协同转运蛋白 2 (SGLT2) 抑制剂已成为 T2DCM 的一种有前途的治疗方法，但精确的构建心脏的心肌细胞、成纤维细胞和内皮细胞的保护机制微环境仍不完全了解，在本次多 PI R01 更新中，我们的团队将阐明这一点。心血管细胞内部和之间的代谢相互作用机制，通过以下方式赋予心脏保护作用：我们将利用诱导多能干细胞 (iPSC) 技术来生成糖尿病模型。对心血管细胞类型进行体外 SGLT2 抑制的细胞和代谢表型分析（目标 1）。构建 iPSC 衍生的工程心脏组织，用于功能表型分析和蛋白质组学测定 SGLT2 抑制剂蛋白相互作用组（目标 2）之后，我们将验证心脏保护机制。单细胞分辨率的糖尿病小鼠模型（目标 3）总之，了解确切的作用和机制。 SGLT2 抑制在 T2DCM 中的作用可能有助于寻找治疗代谢性疾病的新治疗方式心脏病。