Role of CAP in In Vivo Insulin Action

描述（由申请人提供）：2型糖尿病和代谢综合征在美国流行，两者的标志是胰岛素抵抗。了解胰岛素的作用机制对治疗这些疾病至关重要。最近，已经确定了一种信号通路，其将胰岛素刺激其受体与葡萄糖转运独立于PI 3 K联系起来。该途径涉及激活Cbl及其衔接蛋白CAP，并且已知其刺激培养的脂肪细胞中的葡萄糖摄取。除了刺激葡萄糖摄取的作用外，Cbl/CAP复合物还参与巨噬细胞的增殖和运动。由于巨噬细胞活化和慢性炎症与胰岛素抵抗相关，Cbl/CAP的这种双重作用可能具有重要的后果。这个建议的一般目的是检查CAP在调节体内胰岛素作用中的作用。具体目的是1）确定CAP的全身基因敲除是否导致胰岛素作用的改变，2）确定CAP敲除是否导致替代PI 3 K依赖性信号传导途径的上调，和3）确定巨噬细胞浸润、活化和细胞因子产生在CAP敲除小鼠中是否改变，并且是否与胰岛素作用的推定变化相关。

DESCRIPTION (provided by applicant): Type 2 diabetes and the metabolic syndrome are epidemic in the US, and a hallmark of both is insulin resistance. Understanding the mechanisms of insulin action is essential in the treatment of these disorders. Recently, a signaling pathway has been identified that links insulin stimulation of its receptor to glucose transport independent of PI3K. This pathway involves the activation Cbl and its adaptor protein CAP and is known to stimulate glucose uptake in cultured adipocytes. In addition to a role in stimulating glucose uptake, the Cbl/CAP complex is involved in the proliferation and motility of macrophages. As macrophage activation and chronic inflammation have been associated with insulin resistance, this dual role of Cbl/CAP may have important consequences. The general purpose of this proposal is to examine the role of CAP in regulating in vivo insulin action. The specific aims are 1) to determine if whole body gene knockout of CAP results in alterations in insulin action, 2) to determine if CAP knockout results in an upregulation of the alternate PI3K-dependent signaling pathway, and 3) to determine if macrophage infiltration, activation and cytokine production is altered in CAP knockout mice and is related to the putative changes in insulin action.