Exploiting Tie2 Activation for the Treatment of Vascular Diseases

静止内皮表型的丧失是包括糖尿病并发症、败血症和心血管疾病在内的广泛严重疾病的发病和进展的核心。目前缺乏可用于治疗这些疾病血管功能障碍的治疗方法，这强调了开发新治疗方法的必要性。我们认为血管生成素- tie2 /Tek血管信号通路是一个有希望的新靶点。例如，在细胞培养和转基因模型中，血管生成素1的递送可以防止血管泄漏和炎症，同时促进内皮细胞的存活。在重症血管疾病患者中，循环血管生成素（Angpt）水平的改变与发病率和死亡率的增加密切相关。因此，我们假设激活Tie2受体可以恢复糖尿病肾病等疾病状态下的血管静止和功能。为了验证这一假设并测试有效靶向治疗的能力，我们将结合使用强大的遗传动物模型、小分子抑制剂和蛋白质组学策略来确定血管生成素- tie2 /Tek通路在血管疾病中的作用。使用这些方法，我们将首次精确地表征每个主要Angpt配体在Tie2受体激活中的功能和贡献

DESCRIPTION (provided by applicant Loss of the quiescent endothelial phenotype is central to the pathogenesis and progression of a broad spectrum of severe diseases including diabetic complications, sepsis and cardiovascular disease. The current dearth of therapies available to treat vascular dysfunction in these diseases underscores the need to develop new approaches for treatment. We suggest that the Angiopoietin-Tie2/Tek vascular signaling pathway is a promising new target. For example, delivery of Angiopoietin1, prevents vascular leak and inflammation, while promoting endothelial survival in both cell culture and transgenic models. In patients with critical vascular diseases, alterations in circulating Angiopoietin (Angpt) levels ar closely linked to increased morbidity and mortality. Accordingly, we hypothesized that activation of the Tie2 receptor would restore vascular quiescence and function in disease states such as diabetic nephropathy. To test this hypothesis and test the capacity of potent on-target therapies, we will combine studies using robust, genetic animal models, small molecule inhibitors and proteomic strategies for defining the role of the Angiopoietin-Tie2/Tek pathway in vascular diseases. Using these approaches, we will precisely characterize, for the first time, the function(s) and contributions of each of the major Angpt ligands in activation of the Tie2 receptor in the vasculature in vivo, and determine whether inhibition of the phosphatase, VE-PTP, can activate Tie2 in vivo and protect the endothelium from injury in a disease such as diabetes. We will also characterize the complete phosphoproteome of Tie2 and the related ligandless-receptor Tie1, to designate specified vascular functions and effectors for each individual phosphorylation site, ultimately paving the way to improved drug design for vascular dysfunction. Despite the current intense interest in the Angpt-Tie2 pathway by clinicians and pharma, large gaps exist in our knowledge surrounding fundamental aspects of its function(s) at the whole animal, tissue and molecular level. Our studies will provide critical new insights, which are necessary for providing the rationale for supporting clinical applications of this promising therapeutic target.