Impact of Glycemic Control on Extracellular Vesicle-Mediated Angiogenesis in a Porcine Model of Chronic Myocardial Ischemia and Metabolic Syndrome

血糖控制对慢性心肌缺血和代谢综合征猪模型中细胞外囊泡介导的血管生成的影响

• 批准号: 10513302
• 负责人: Sharif A. Sabe
• 金额: $ 7.61万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513302
• 关键词: Affect; Animal Model; Animals; Blood capillaries; Cardiac; Catheters; Cell Therapy; Chronic; Clinical; Clinical Trials; Complex; Complication; Complications of Diabetes Mellitus; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Diffuse; Endothelial Cells; Family suidae; Fellowship; Foundations; Functional disorder; Glucose; Glucose Transporter; Goals; Growth; Health; Heart Diseases; Heart failure; Hour; Human; Hyperlipidemia; Hypertension; Hypoxia; Innovative Therapy; Intervention; Knowledge; Left; Life; MAP Kinase Gene; Mediating; Medical; Metabolic syndrome; Metformin; Mission; Modeling; Molecular; Mus; Myocardial Ischemia; Myocardial perfusion; Operative Surgical Procedures; Patients; Persons; Placebos; Proteins; Proteomics; Public Health; Reactive Oxygen Species; Research; Research Project Grants; Role; Scientist; Signal Pathway; Signal Transduction; Surgeon; Testing; Therapeutic; Training; United States National Institutes of Health; Vascular Endothelial Growth Factors; ameroid; angiogenesis; base; bone marrow mesenchymal stem cell; career; clinically relevant; comorbidity; constriction; density; diabetic patient; disability; experimental study; extracellular vesicles; glycemic control; heart function; improved; innovation; porcine model; preclinical study; protein expression; regenerative therapy; response; skills

Therapeutic options for end-stage, diffuse coronary artery disease (CAD), an important complication of diabetes,1,2 remain limited. Regenerative therapies, including extracellular vesicles (EV), are promising therapeutic options for diabetic patients with severe CAD who have failed other interventions. While animal- based studies of cell therapy have been promising, clinical trials have failed to demonstrate similar efficacy in CAD.5–7 This discrepancy may be due to altered signaling in the setting of metabolic syndrome (MS). The long term goal of the applicant in pursuing this research fellowship is to develop a strong foundation and core skill set in academic cardiothoracic research, with which he can launch a career as a cardiac surgeon scientist after completing surgical clinical training. The overall objective of this project is to elucidate the molecular mechanisms involved in EV-induced coronary collateral development in ischemic myocardium in a clinically relevant porcine model of MS, specifically identifying the role of glycemic control in augmenting EV-induced angiogenesis. The central hypothesis is that glycemic control will reduce reactive oxygen species (ROS), alter AMP:ATP ratio, and increase VEGF-induced PI3K-Akt signaling, allowing for augmented EV-mediated angiogenesis. The central hypothesis will be tested by pursuing two specific aims: 1) Identify the effects of glycemic control on key signaling pathways involved in coronary angiogenesis and collateralization response of ischemic myocardium to human bone marrow mesenchymal stem cell (HBMSC) derived EVs in a porcine model of MS; 2) Identify the effects of hypoxia-modified HBMSC-derived EVs containing increased levels of VEGF/HGF, glucose transporter SLC2A14, and Akt, on coronary angiogenesis and myocardial perfusion in chronically ischemic myocardium in a porcine model of MS, with and without glycemic control. For both aims, a porcine model of diet-induced MS and chronic myocardial ischemia using left circumflex ameroid constriction will be used. Swine with MS and chronic myocardial ischemia with and without glycemic control using metformin will be injected (intracardiac) with HBMSC-EV vs hypoxia-modified HBMSC-EV vs placebo. Analysis will be performed on molecular expression of proteins involved in angiogenesis signaling, vessel density, myocardial perfusion, and cardiac function. The research proposed in this application is innovative because it investigates the use of HBMSC-EV to treat chronically ischemic myocardium in a clinically relevant large animal model of metabolic syndrome, which more accurately reflects the complex pathophysiology and co-morbidities in human patients. The proposed research is significant because it is expected to identify clinically relevant therapeutic strategies that can enhance the angiogenic response of chronically ischemic myocardium to HBMSC-EV. Ultimately, such knowledge may contribute to the development of innovative therapies for patients with chronic myocardial ischemia, aligning with the NIH mission to enhance health, lengthen life, and reduce illness and disability.

终末期弥漫性冠状动脉疾病（CAD）的治疗选择