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.

终阶段，弥漫性冠状动脉疾病（CAD）的治疗选择，这是一个重要的并发症 糖尿病，1,2仍然有限。再生疗法，包括细胞外蔬菜（EV），有希望 针对其他干预措施失败的严重CAD糖尿病患者的治疗选择。而动物 - 已承诺基于细胞疗法的研究，临床试验未能证明相似的效率 CAD.5–7此差异可能是由于代谢综合征（MS）的信号改变所致。长 申请人追求这项研究奖学金的一项目标是建立强大的基础和核心技能 在学术心理研究中进行，他可以通过该研究以心脏外科医生的职业生涯 完整的手术临床训练。该项目的总体目的是阐明分子 诊所中缺血性心肌中电动汽车诱导的冠状动脉副发育涉及的机制 MS的相关猪模型，专门识别血糖控制在增强EV诱导的 血管生成。中心假设是血糖控制将减少活性氧（ROS），改变 AMP：ATP比率，并增加VEGF诱导的PI3K-AKT信号，允许增强EV介导 血管生成。中心假设将通过追求两个具体目标来检验：1）确定的影响 对参与冠状动脉造成冠状血管生成的关键信号通路的血糖控制和抵押反应 在猪模型中衍生的EVS的缺血性心肌到人骨髓间充质干细胞（HBMSC） MS; 2）确定含有增加水平的HBMSC衍生的低氧改性HBMSC的影响 VEGF/HGF，葡萄糖转运蛋白SLC2A14和AKT，冠状血管生成和心肌灌注 在有或没有血糖控制的MS猪模型中，慢性缺血性心肌。对于两个目标， 饮食诱导的MS和慢性心肌缺血的猪模型，使用左弯曲的双星收缩将 被使用。具有MS和慢性心肌缺血的猪具有和不使用二甲双胍的血糖控制 将HBMSC-EV与缺氧修饰的HBMSC-EV与安慰剂注射（心内）。分析将是 对参与血管生成信号，血管密度，心肌的分子表达进行 灌注和心脏功能。本应用程序中提出的研究具有创新性，因为它研究了 使用HBMSC-EV在临床相关的大型动物模型中使用HBMSC-EV治疗慢性缺血性心肌 代谢综合征，它更准确地反映了人类复杂的病理生理学和合并症 患者。拟议的研究很重要，因为它有望识别临床相关的治疗性 可以增强长期缺血性心肌对HBMSC-EV的血管生成反应的策略。 最终，这种知识可能有助于为患有慢性患者的创新疗法发展 心肌缺血，符合NIH的使命，以增强健康，延长寿命并减少疾病和 残疾。