Role of dopamine in the regulation of endothelial cell functions in diabetes

描述(申请人提供)：在糖尿病患者中，外周循环中功能障碍的内皮细胞(EC)和低数量的内皮祖细胞(EPC)会导致几种血管疾病，如伤口愈合受阻。最近的报道表明，活性氧(ROS)和细胞因子基质细胞衍生因子-1(SDF-1)的低表达是这些病理状态的重要原因。由于神经递质多巴胺(DA)被报道调节ROS的产生，而且DA也可能控制SDF-1的合成，因此我们假设DA可以使糖尿病创面组织的EC功能和SDF-1的表达正常化。目的1探讨DAD1受体在ROS诱导的EC功能中的作用。在目标2中，将确定DA D1受体在巨噬细胞产生SDF-1中的作用，最后将在目标3中检测DA D1受体对糖尿病创面组织中ROS产生和新生血管的影响。 与公共卫生相关：糖尿病患者内皮细胞功能障碍和生长因子和细胞因子的产生显著减少，导致多种血管疾病，如创面修复和愈合受损。根据疾病控制和预防中心的数据，尽管伤口护理取得了进展，但糖尿病难治性伤口每年导致超过72,000例截肢，因此这一应用的目标是开发多巴胺介导的新的有效疗法来治疗这种病理情况。

DESCRIPTION (provided by applicant): In diabetes mellitus, dysfunctional endothelial cells (EC) and low numbers of endothelial progenitor cells (EPC) in the peripheral circulation lead to several vascular disorders like impaired wound healing. Recent reports indicate reactive oxygen species (ROS) and low expression of the cytokine, stromal cell-derived factor-1¿ (SDF-1¿) to be important causes of these pathological conditions. As neurotransmitter dopamine (DA) is reported to regulate ROS production and because DA may also control SDF-1¿ synthesis, we therefore hypothesized that DA could normalize EC functions and SDF-1¿ expression in diabetic wound tissues. Aim 1 will investigate the effect of DA D1 receptors on ROS induced EC functions. In Aim 2, the role of DA D1 receptors on SDF-1¿ production by macrophages will be determined and finally Aim 3 will examine the effects of DA D1 receptors on ROS production and neovascularization in diabetic wound tissues. PUBLIC HEALTH RELEVANCE: Endothelial cell dysfunctions and significantly decreased production of growth factors and cytokines in diabetes mellitus lead to several vascular disorders like impaired wound repair and healing. According to the Center for Disease Control and Prevention, refractory diabetic wounds lead to over 72,000 amputations each year despite of advances in wound care, therefore the goal of this application is to develop dopamine mediated newer and an effective therapy for this pathological condition.