GLYCOSPHINGOLIPIDS IN DIABETES MELLITUS

糖尿病中的糖鞘脂

• 批准号: 2141783
• 负责人: JAMES ALAN SHAYMAN
• 金额: $ 21.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2141783
• 关键词: cell cell interaction; ceramides; diabetes mellitus; enzyme activity; gas chromatography; glucose metabolism; glycosphingolipids; hyperglycemia; insulinlike growth factor; kidney metabolism; laboratory rabbit; lipid metabolism; phosphatidylinositols; protein kinase C; thin layer chromatography; tissue /cell culture

Sphingolipids have historically been studied in the setting of rare genetic disorders where these compounds accumulate due to a defect in an enzyme or activator for their metabolism. However, more recent studies have identified several potential functional roles for sphingolipids, including mediators of intracellular signaling events or of cell-cell interactions. From these studies it has been proposed that sphingolipids play a role in the pathophysiology of more common disorders such as cancer or infection. We have studied the role of sphingolipids in another common disorder, diabetes mellitus, and have observed that hyperglycemia results in increased levels of renal glycosphingolipids in concert with the early hypertrophic changes of diabetic nephropathy. Hyperglycemia-induced changes in renal glycosphingolipid formation are observed in both the kidneys of streptozotocin-treated rats and in renal proximal tubule cells. Pharmacological inhibition of glucosylceramide synthesis reverses the early renal hypertrophy in diabetic kidneys and the proliferative response of proximal tubular epithelial cells cultured in hyperglycemia medium, consistent with the existence of a biochemical link between glycosphingolipids and diabetic nephropathy. We propose as the major hypothesis for this grant that the renal growth accompanying early diabetic hypertrophy is mediated by altered sphingolipid metabolism. The specific aims of this proposal are: 1. To characterize the nature of the relationship between hyperglycemia and the rate of glycosphingolipid synthesis. 2. To define the role of individual sphingolipids in mediating the growth response to hyperglycemia. 3. To determine the role of changes in sphingolipid content in regulating IGF-1-stimulated cellular proliferation and cell cycle progression.

鞘脂从历史上进行了研究 这些化合物由于缺陷而积累的遗传疾病 其代谢的酶或激活剂。但是，最近的研究 已经确定了鞘脂的几个潜在功能作用， 包括细胞内信号事件或细胞细胞的介体 互动。从这些研究中，有人提出了鞘脂 在癌症等更常见疾病的病理生理学中发挥作用 或感染。我们研究了鞘脂在另一个常见中的作用 疾病，糖尿病，并观察到高血糖结果 在与早期共同协同的肾糖磷脂脂的水平上增加 糖尿病肾病的肥厚性变化。高血糖引起的 在这两个 链蛋白酶治疗的大鼠和肾近端小管细胞中的肾脏。 药理学抑制葡萄糖酰亚胺合成的逆转 糖尿病肾中的早期肾脏肥大和增生反应 在高血糖培养基中培养的近端管状上皮细胞的 与存在的生化连接一致 糖脂果脂和糖尿病性肾病。我们建议作为专业 这笔赠款的假设是伴随着早期的肾脏增长 糖尿病肥大是通过改变的鞘脂代谢介导的。 该提案的具体目的是： 1。表征高血糖之间关系的性质 以及糖磷脂合成的速率。 2。定义单个鞘脂在介导生长中的作用 对高血糖的反应。 3。确定变化在调节鞘脂含量中的作用 IGF-1刺激的细胞增殖和细胞周期进程。