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

PKC以同工酶特异性的方式调节一系列不同的细胞过程。最近有强有力的证据表明，PKC，尤其是PKC参与了糖尿病中葡萄糖的作用。这包括葡萄糖在糖尿病动物的肾小球、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，用PKC特异性抑制剂LY333531抑制PKC_，可阻断葡萄糖的作用。最近，我们的研究小组设计并合成了一类新型的多不饱和脂肪酸。其中MP5(_-oxa-21：3n-3)能抑制高糖诱导的PKC？在培养的系膜细胞以及糖尿病大鼠的肾小球中以相对选择性的方式表达。这项建议的总体目标是评估一种通过化学工程设计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可能性。其具体目的是：1.研究MP5对葡萄糖或晚期糖基化终产物刺激的蛋白激酶C(PKC)活化的影响。2.确定MP5的酯化反应是否对MP5的作用是必需的。3.研究MP5在体外是否能有效地阻止葡萄糖的作用，如葡萄糖刺激系膜细胞产生转化生长因子β，以及体内链脲佐菌素糖尿病小鼠的作用。

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