Microparticles and microvascular dysfunction in diabetes

糖尿病中的微粒和微血管功能障碍

• 批准号: 8996443
• 负责人: PINGNIAN HE
• 金额: $ 31.9万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996443
• 关键词: Microparticles; microvascular; dysfunction; diabetes

DESCRIPTION (provided by applicant): Diabetes is one of the leading causes of mortality in the US and more than half of diabetic patients have cardiovascular complications. However, the mechanisms and the critical factors involved in the development of diabetic vascular complications remain poorly understood. Our recent studies found that microvessels in diabetic rats had increased basal permeability and a markedly augmented permeability response to inflammatory mediators. We also found that circulating microparticles (MPs), the small vesicles released from the cell surface upon activation, were significantly elevated in both diabetic patients and diabetic rats. Most importantly, results derived from our newly developed experiments showed that transfusion of diabetic rat plasma into the circulation of a normal rat causes immediate leukocyte adhesion and increased microvessel permeability, and that removal of MPs from the diabetic plasma abolished the effect, indicating an important role of diabetic MPs in mediating microvascular inflammation. Similar observations were replicated when isolated diabetic MPs were directly perfused into a normal individual microvessel. In addition, MP analysis of diabetic patients' plasma showed a positive correlation between the levels of MPs and their vascular complications. These novel preliminary findings led us to hypothesize that the increased levels of MPs under diabetic conditions are not simply the results of vascular cell activation and apoptosis, but are also vectors that disseminate pro- inflammatory and pro-coagulant mediators throughout the vascular system, exacerbating vascular dysfunction. This application aims to test this hypothesis with three specific aims. Aim 1 is to characterize the cellular sources and identify the mechanisms of increased MPs under diabetic conditions. Aim 2 is to investigate the causal relationship between the increased plasma MPs and the inflammatory manifestation of diabetic microvessels and to identify the mechanisms involved in MP- mediated leukocyte adhesion, thrombus formation, and increased microvessel permeability. Aim 3 is to investigate the correlations between the increased MPs and the clinical status of diabetic patients. We will evaluate the potential of using MP analysis to predict the ris or severity of vascular complications, as well as the efficacy of diabetic therapies. Present knowledge about MPs is largely derived from in vitro studies. Our unique experimental approaches that combine flow cytometry analysis of MPs with single vessel perfusion, plasma transfusion, confocal imaging, electron microscopy, and quantitative permeability measurements in intact microvessels, will provide the most needed in vivo mechanisms of diabetic MP- mediated microvascular inflammation. The direct linkage between laboratory animal findings with patient disease conditions assures that the knowledge gained from the proposed studies will provide new insight into the pathogenesis of diabetes-associated vascular dysfunction and benefit targeted therapies.

描述（由申请人提供）：糖尿病是美国死亡率的主要原因之一，超过一半的糖尿病患者患有心血管并发症。然而，糖尿病血管并发症发展所涉及的机制和关键因素仍然了解不足。我们最近的研究发现，糖尿病大鼠的微血管的基础渗透性增加，并且对炎症介质的渗透性反应显着增加。我们还发现，在激活后从细胞表面释放的小囊泡循环微粒（MPS）在糖尿病患者和糖尿病大鼠中均显着升高。 Most importantly, results derived from our newly developed experiments showed that transfusion of diabetic rat plasma into the circulation of a normal rat causes immediate leukocyte adhesion and increased microvessel permeability, and that removal of MPs from the diabetic plasma abolished the effect, indicating an important role of diabetic MPs in mediating microvascular inflammation.将分离的糖尿病MP直接灌注到正常的单个微血管中时，复制了类似的观察结果。此外，对糖尿病患者血浆的MP分析显示，MPS的水平与其血管并发症之间存在正相关。这些新颖的初步发现使我们假设糖尿病条件下的MPS的水平增加不仅是血管细胞激活和凋亡的结果，而且还是载体，它们在整个血管系统中传播了促炎性和促凝的介体，整个血管系统，使血管功能障碍恶化。该应用程序旨在以三个特定目标检验这一假设。目的1是表征细胞来源并确定在糖尿病条件下MPS增加的机制。 AIM 2是研究增加的血浆MPS与糖尿病微血管的炎症表现之间的因果关系，并确定参与MP介导的白细胞粘附，血栓形成和微分解剂增加的机制。目标3是研究MPS增加与糖尿病患者临床状况之间的相关性。我们将评估使用MP分析预测血管并发症的RI或严重程度的潜力，以及糖尿病疗法的疗效。关于MP的当前知识主要来自体外研究。我们将MPS流式细胞术与单血管灌注，血浆输血，共聚焦成像，电子显微镜以及完整微量微调的定量通透性测量结合的独特实验方法将提供糖尿病介导的MP介导的MP-介导的MP-介导的MP-微血管微血管炎症的体内机制。实验室动物发现与患者疾病状况之间的直接联系确保了拟议的研究所获得的知识将为糖尿病相关血管功能障碍的发病机理提供新的见解和靶向靶向疗法。