ELEVATED GLUCOSE EFFECTS ON CYTOKINE MEDIATED ENDOTHELIAL LEUKOCYTE/INTERACTION

葡萄糖升高对细胞因子介导的内皮白细胞/相互作用的影响

• 批准号: 2781148
• 金额: $ 9.13万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2781148
• 关键词: animal tissue; biological signal transduction; calcium flux; cell adhesion molecules; cell cell interaction; cell migration; cytokine; diabetes mellitus; disease /disorder proneness /risk; enzyme linked immunosorbent assay; hyperglycemia; infection; interleukin 1; leukocytes; medical complication; scintillation spectrometry; statistics /biometry; thin layer chromatography; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium

Infections in diabetes mellitus patients are more common and severe than in the general population. The susceptibility to infections in these patients has been associated with neutrophil dysfunction and more recently to an impaired leukocyte-endothelial interaction. Adhesion of leukocytes is an early and determinant event for an effective inflammatory or immune response. Leukocyte-endothelial interaction is enhanced by signals from blood borne activators, i.e. cytokines. Hyperglycemia is one of the most important risk factors leading to chronic complications in diabetes mellitus. Although suggested, the contribution of hyperglycemia to an impaired leukocyte-endothelial interaction in diabetic patients, has not been conclusively established. Since alterations in phosphoinositide metabolism is one of the proposed molecular mechanisms through which elevated glucose exerts its pathologic effect it seems relevant to explore this transduction process more closely. This project aims to study the effect of elevated glucose levels on the cytokine-induced signaling that permits the endothelial-leukocyte interaction necessary for the inflammatory response. A microvascular derived cell culture (i.e. bovine retina) will be used as the experimental model. Cytokine-induced signaling in endothelial cells will be followed through the determination of the generation of diacylglycerol in 3H-arachidonic acid labeled cultured cells; determination of production of inositol phosphates from 3H- myoinositol labeled cells and intracellular Ca2+ mobilization in FURA-AM loaded cells. Signaling will be correlated with endothelial-leukocyte interaction detected through the expression of cell adhesion molecules and leukocyte adherence tests. This study will expand our understanding of the biochemical mechanisms through which hyperglycemia alters the physiological response of target tissues such as the vascular endothelium, in particular its contribution to the increased susceptibility of diabetic patients to infections. The results obtained may eventually lead to therapeutic measures intended to prevent the appearance of chronic complications in diabetes mellitus patients.

糖尿病患者的感染比 在普通人群中。在这些地区对感染的敏感性 患者一直与中性粒细胞功能障碍有关，最近 导致白细胞-内皮细胞相互作用受损。白细胞粘附性 对于有效的炎症或免疫来说是一个早期的决定性事件 回应。白细胞与内皮细胞的相互作用受到以下信号的增强 血源性激活剂，即细胞因子。高血糖是最常见的 糖尿病慢性并发症的重要危险因素 糖尿病。尽管有建议，但高血糖对高血压的贡献 糖尿病患者白细胞-血管内皮细胞相互作用受损 都是确凿的证据。由于磷脂酰肌醇的变化 代谢是已提出的分子机制之一，通过它 高血糖发挥其病理效应似乎与探讨有关 这一转导过程更加紧密。这个项目的目的是研究 血糖水平升高对细胞因子诱导的信号转导的影响 允许血管内皮细胞-白细胞相互作用 炎症反应。微血管衍生细胞培养(即牛 视网膜)作为实验模型。细胞因子诱导的信号传导 将通过测定血管内皮细胞中的 ~3H-花生四烯酸标记培养体系中甘油二酯的生成 细胞.从~3H-磷酸生产肌醇的测定 Fura-AM肌醇标记细胞与细胞内钙离子动员 加载的单元格。信号转导将与内皮-白细胞相关 通过表达细胞黏附分子和 白细胞黏附试验。这项研究将扩大我们对 高血糖改变心脏功能的生化机制 靶组织的生理反应，如血管内皮细胞， 尤其是它对糖尿病易感性增加的贡献 患者对感染的反应。所获得的结果可能最终导致 旨在预防慢性病出现的治疗措施 糖尿病患者的并发症。