Exploiting Tie2 Activation for the Treatment of Vascular Diseases

描述(由申请人提供)静止性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一系列严重疾病的发病和进展的核心。目前缺乏治疗这些疾病的血管功能障碍的治疗方法，这突显了开发新的治疗方法的必要性。我们认为Angiopoietin-Tie2/Tek血管信号通路是一个有前景的新靶点。例如，血管生成素1的传递可以防止血管泄漏和炎症，同时促进细胞培养和转基因模型中的内皮细胞存活。在危重血管疾病患者中，循环血管生成素(Angpt)水平的变化与发病率和死亡率的增加密切相关。因此，我们假设Tie2受体的激活将在糖尿病肾病等疾病状态下恢复血管静止和功能。为了验证这一假设并测试有效的靶向治疗的能力，我们将结合使用稳健的遗传动物模型、小分子抑制剂和蛋白质组策略的研究，以确定血管生成素-Tie2/Tek通路在血管疾病中的作用。利用这些方法，我们将第一次准确地表征每一个主要的Angpt配体在激活Tie2受体中的功能(S)和贡献 在体内的血管系统中，并确定抑制磷酸酶VE-PTP是否可以在体内激活Tie2并保护内皮免受糖尿病等疾病的损伤。我们还将描述Tie2和相关的无配体受体Tie1的完整磷酸蛋白质组，为每个单独的磷酸化位点指定特定的血管功能和效应器，最终为改进治疗血管功能障碍的药物设计铺平道路。尽管目前临床医生和制药商对Angpt-Tie2途径非常感兴趣，但在整个动物、组织和分子水平上，我们对其功能的基本方面的了解仍存在很大差距(S)。我们的研究将提供重要的新见解， 为支持这一有希望的治疗靶点的临床应用提供理论基础是必要的。

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.