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（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