Exploiting Tie2 Activation for the Treatment of Vascular Diseases

描述（由申请人提供）静息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多种严重疾病的发病机制和进展的核心。目前缺乏治疗这些疾病中血管功能障碍的疗法，这强调了开发新的治疗方法的必要性。我们认为血管生成素-Tie 2/Tek血管信号通路是一个有前途的新靶点。例如，血管生成素1的递送防止血管渗漏和炎症，同时促进细胞培养物和转基因模型中的内皮存活。在危重血管疾病患者中，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Tie 2受体的激活将恢复疾病状态如糖尿病肾病中的血管静止和功能。为了检验这一假设并测试有效靶向治疗的能力，我们将使用稳健的遗传动物模型、小分子抑制剂和蛋白质组学策略来确定血管生成素-Tie 2/Tek通路在血管疾病中的作用，从而将联合收割机研究结合起来。使用这些方法，我们将首次精确地表征每种主要Angpt配体在Tie 2受体活化中的功能和贡献 在体内的血管系统中，并确定磷酸酶VE-PTP的抑制是否可以在体内激活Tie 2并保护内皮免受疾病如糖尿病的损伤。我们还将表征Tie 2和相关无配体受体Tie 1的完整磷酸化蛋白质组，以指定每个磷酸化位点的特定血管功能和效应物，最终为改善血管功能障碍的药物设计铺平道路。尽管临床医生和制药公司目前对Angpt-Tie 2通路非常感兴趣，但我们在整个动物，组织和分子水平上对其功能的基本方面的知识存在很大差距。我们的研究将提供重要的新见解， 是必要的，为支持这一有前途的治疗靶点的临床应用提供理论基础。

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.