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，这是一种重要的并发症 糖尿病，1,2 再生疗法，包括细胞外囊泡 (EV)，前景广阔。 患有严重 CAD 且其他干预措施失败的糖尿病患者的治疗选择。 细胞疗法的基础研究一直很有希望，但临床试验未能证明在 CAD.5–7 这种差异可能是由于代谢综合征 (MS) 情况下的信号改变所致。 申请人追求这项研究奖学金的学期目标是打下坚实的基础和核心技能 从事学术心胸研究，之后他可以开始作为一名心脏外科医生科学家的职业生涯 完成外科临床培训该项目的总体目标是阐明分子机制。 临床上 EV 诱导缺血心肌冠状动脉侧支发育的机制 相关的 MS 猪模型，特别确定了血糖控制在增强 EV 诱导的作用中的作用 中心假设是血糖控制会减少活性氧（ROS），改变。 AMP:ATP 比率，并增加 VEGF 诱导的 PI3K-Akt 信号传导，从而增强 EV 介导的 中心假设将通过追求两个具体目标来检验：1）确定血管生成的影响。 血糖控制涉及冠状动脉血管生成和侧支反应的关键信号通路 猪模型中缺血心肌与人骨髓间充质干细胞 (HBMSC) 衍生的 EV 2) 确定缺氧修饰的 HBMSC 衍生的 EV 的影响，其中含有增加的水平 VEGF/HGF、葡萄糖转运蛋白 SLC2A14 和 Akt 对冠状动脉血管生成和心肌灌注的影响 多发性硬化症猪模型中的慢性缺血性心肌，有或没有血糖控制 对于这两个目标， 使用左旋美罗缩肌建立饮食诱导的 MS 和慢性心肌缺血的猪模型 将使用患有 MS 和慢性心肌缺血的猪，无论是否使用二甲双胍控制血糖。 注射（心内）HBMSC-EV 与缺氧改良 HBMSC-EV 对比安慰剂 分析将如下。 对参与血管生成信号、血管密度、心肌的蛋白质的分子表达进行研究 本申请中提出的研究具有创新性，因为它调查了。 使用 HBMSC-EV 在临床相关的大型动物模型中治疗慢性缺血性心肌 代谢综合征，更准确地反映了人类复杂的病理生理学和合并症 拟议的研究意义重大，因为它有望确定临床相关的治疗方法。 可以增强慢性缺血心肌对 HBMSC-EV 的血管生成反应的策略。 最终，这些知识可能有助于开发针对慢性病患者的创新疗法 心肌缺血，符合 NIH 增强健康、延长寿命和减少疾病的使命 残疾。