THIOREDOXIN-INTERACTING PROTEIN IN ENDOTHELIAL AND ORGANISMAL METABOLISM

alpha arrestin家族包括研究得最好的成员Txnip和其他五种功能未知的蛋白质。Txnip最初被认为是血管氧化还原状态的调节剂。由于Txnip是由高血糖诱导的，并且Txnip可以抑制硫氧还蛋白，许多研究者提出高血糖通过Txnip介导的硫氧还蛋白抑制来诱导氧化应激。然而，令人信服的证据表明，Txnip是与血管疾病相关的多种信号事件的关键调节剂。 由于Txnip可以与还原的硫氧还蛋白（但不氧化）形成混合二硫键复合物， 因此，Txnip可以作为氧化还原敏感性信号传导调节剂而不是简单地作为硫氧还蛋白的抑制剂发挥作用。我们的初步数据表明，Txnip是葡萄糖和脂质代谢，胰岛素敏感性，脂肪形成和能量平衡的重要介质。在这里，我们提出的数据支持的中心假设，Txnip是一个关键的细胞内信号调节，Txnip的功能是不可能仅仅是由于抑制硫氧还蛋白。我们提出了三个Alms，将定义Txnip在内皮细胞中的作用：AIM 1。明确Txnip和硫氧还蛋白相互作用在内皮细胞炎症反应中的作用。在这里，我们将测试的假设，Txnip在调节血管炎症反应的作用是依赖于特定的分子相互作用与硫氧还蛋白通过分子间二硫键。AIM 2.明确Txnip的结构-功能关系。我们提出了Txnip的特定结构域调节葡萄糖代谢的初步数据;使用β抑制蛋白的已知结构， 我们将定义Txnip的特定区域以及调节葡萄糖代谢和内皮剪切应力反应的其它α抑制蛋白。目的3：验证Txnip通过PPAR-gamma依赖性机制调节内皮细胞代谢的假说。我们将确定Txnip对PPAR-gamma功能的影响是否依赖于硫氧还蛋白，并检验Txnip在体内因果影响PPAR-gamma功能的假设。最后，我们将在体内探索Txnip影响PPAR-gamma功能以通过内皮细胞表达介导全身代谢调节的概念。

The alpha arrestin family includes the best studied member, Txnip, and five other proteins with unknown functions. Txnip was originally considered a regulator of vascular redox state. Because Txnip is induced by hyperglycemia, and Txnip can inhibit thioredoxin, many investigators have proposed that hyperglycemia Induces oxidative stress through Txnip-mediated inhibition of thioredoxin. However, compelling evidence has now emerged that Txnip is a critical regulator of diverse signaling events relevant to vascular disease. Because Txnip can form a mixed disulfide complex with reduced thioredoxin (but not oxidized thioredoxin),Txnip may function as a redox-sensitive signaling regulator rather than simply as an inhibitor of thioredoxin. Our preliminary data show that Txnip is an important mediator of glucose and lipid metabolism, insulin sensitivity, adipogenesis, and energy balance. Here we present data supporting the central hypothesis that Txnip is a critical intracellular signaling regulator, and that Txnip's functions are unlikely to be solely due to inhibition of thioredoxin. We propose three Alms that will define the role of Txnip in endothelial cells: AIM 1. To define the role of the interaction of Txnip and thioredoxin in the inflammatory response of endothelial cells. Here we will test the hypothesis that the role of Txnip In the regulation of the vascular inflammatory response is dependent on the specific molecular interaction with thioredoxin through an Intermolecular disulfide bond. AIM 2. To define structure-function relations of Txnip. We present preliminary data that specific domains of Txnip regulate glucose metabolism; using the known structure of beta arrestins, we will define specific regions of Txnip as well as other alpha arrestins that regulate glucose metabolism and the endothelial shear stress response. AIM 3:To test the hypothesis that Txnip regulates metabolism in vivo via a PPAR-gamma dependent mechanism in endothelial cells. We will determine whether Txnip's ihipact on PPAR-gamma function is dependent on thioredoxin and test the hypothesis that Txnip causally influences PPAR-gamma function in vivo. Finally, we will explore in vivo the concept that Txnip impacts PPAR-gamma function to mediate whole body metabolic regulation through endothelial cell expression.