Fox proteins mediate insulin-increasedPAI-1 transcription

描述（由申请人提供）：pai -1在糖尿病中的过度表达可能是糖尿病所有主要并发症的核心；视网膜病变，肾病，神经病变，伤口愈合和大血管疾病。它是发育、组织迁移、组织重塑和细胞粘附所必需的成分，也是蛋白酶激活的有效抑制剂。在糖尿病中，由于胰岛素和氧化应激的转录增加，其产生高度失调。了解胰岛素和氧化应激如何激活PAI-1启动子以及其活性如何在糖尿病中正常化是至关重要的。高胰岛素血症是II型糖尿病的关键变化之一，而1型糖尿病患者和胰岛素治疗暴露于胰岛素药理学水平。最近人们认识到，虽然细胞对胰岛素的代谢作用产生抵抗，但胰岛素的有丝分裂作用仍然是胰岛素反应性的。这导致葡萄糖转运和胰岛素代谢的双重缺陷，而胰岛素应答基因的转录被过度激活。PAI-1就是这样一种胰岛素激活基因。PAI-1启动子也对氧化应激有反应，氧化应激是糖尿病病理的一部分，胰岛素和氧化应激共同产生PAI-1生成的增加。我们已经定义了PAI-1启动子的胰岛素应答元件，并确定激活该元件的胰岛素激活转录因子是forkhead相关转录因子。我们还确定氧化应激激活AP-1反应元件，该元件与胰岛素反应元件相邻。这是通过JNK/SAPK的激活和c-jun的磷酸化来实现的，这增加了AP1复合物与PAI-1启动子的结合。胰岛素和氧化应激诱导了转录的加性激活。确定介导启动子胰岛素反应的Forkhead相关转录因子，并确定其如何被胰岛素激活是很重要的。这项建议提出了实现这些目标的战略。

DESCRIPTION (provided by applicant): PAI-1over expression in diabetes may be central to all of the major complications of diabetes; retinopathy, nephropathy, neuropathy, wound healing and macrovascular disease. It is a required component in development, tissue migration, tissue remodeling and cell adhesion as well as being a potent inhibitor of protease activation. Its production is highly disregulated in diabetes due to increased transcription in response to insulin and oxidative stress. It is essential to understand how insulin and oxidative stress activate the PAI-1 promoter and how its activity can be normalized in diabetes. Hyperinsulinemia is one of the key changes in type II diabetes while patients with type I diabetes and treated with insulin are exposed to pharmacological insulin levels. It has recently become appreciated that although cells become resistant to the metabolic effects of insulin, the mitogenic effects of insulin remain insulin responsive. This results in a double defect with glucose transport and metabolism becoming refractory to insulin while transcription of insulin responsive genes is hyperactivated. PAI-1 is one such insulin-activated gene. The PAI-1 promoter is also responsive to oxidative stress that is part of the pathology of diabetes and insulin and oxidative stress combine to produce an additive increase in PAI-1 production. We have defined the insulin response element of the PAI-1 promoter and have determined that the insulin activated transcription factor that activates this element is a Forkhead-related transcription factor. We have also determined that oxidative stress activates an AP-1 response element that is adjacent to the insulin response element. This is accomplished through activation of JNK/SAPK and phosphorylation of c-jun that increases binding of the AP1 complex to the PAI-1 promoter. Insulin and oxidative stress induce an additive activation of transcription. It is important to identify the Forkhead related transcription factor that mediates the insulin response of the promoter and to determine how it is activated by insulin. This proposal sets forth a strategy for accomplishing these goals.