Targeting protein kinase C in diabetes management using novel polyunsaturated fatty acids

使用新型多不饱和脂肪酸在糖尿病管理中靶向蛋白激酶 C

• 批准号: nhmrc : 250483
• 负责人: A/Pr Charles Hii
• 金额: $ 10万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Development Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/targeting-protein-kinase-fatty-acids/78334
• 关键词: Targeting; protein; kinase; diabetes; management

PKC regulates a diverse range of cellular processes in an isozyme-specific manner. There is strong recent evidence to implicate PKC, especially PKC _, in mediating the actions of glucose in diabetes. This includes the action of glucose in renal glomeruli, retina, aorta and heart of diabetic animals and in cultured cells from these organs. More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531, blocks the actions of glucose. Recently, our research group designed and synthesised a family of novel polyunsaturated fatty acids. One of these, MP5 (_-oxa- 21:3n-3), inhibited high glucose-induced activation of PKC? in cultured mesangial cells as well as in glomeruli of diabetic rats in a relatively selective manner. The overall aim of this proposal is to evaluate the potential for a chemically engineered novel polyunsaturated fatty acid, MP5 (_-oxa-21:3n-3), to treat pathogenesis associated with diabetes by targeting the PKC system. The specific aims are to: 1. Characterise the effects of MP5 on glucose- or advanced glycosylation end product-stimulated activation of protein kinase C (PKC). 2. Determine whether esterification of MP5 into diacylglycerol is essential for the action of MP5 3. Investigate whether MP5 is efficacious at preventing the actions of glucose in vitro e.g. glucose stimulated TGF_ production in mesangial cells, and in vivo in streptozotocin-diabetic r

PKC以同工酶特异性的方式调节多种细胞过程。最近有强有力的证据表明PKC，特别是pkc_在糖尿病中介导葡萄糖的作用。这包括葡萄糖在糖尿病动物肾小球、视网膜、主动脉和心脏以及这些器官的培养细胞中的作用。更重要的是，PKC_特异性抑制剂LY333531抑制PKC_可以阻断葡萄糖的作用。最近，我们课题组设计并合成了一类新型多不饱和脂肪酸。其中之一，MP5 (_-oxa- 21:3n-3)，抑制高糖诱导的PKC？在糖尿病大鼠培养的系膜细胞和肾小球中以相对选择性的方式。本提案的总体目标是评估化学工程的新型多不饱和脂肪酸MP5 （_-oxa-21:3n-3）通过靶向PKC系统治疗糖尿病相关发病机制的潜力。具体目标是：1。表征MP5对葡萄糖或晚期糖基化终产物刺激的蛋白激酶C （PKC）激活的影响。2. 确定MP5酯化成二酰基甘油对mp5.3的作用是否必要。研究MP5是否在体外有效地阻止葡萄糖的作用，如葡萄糖刺激肾小球系膜细胞产生TGF_，在体内是否有效地阻止链脲佐菌素-糖尿病r