Discovering novel atypical PKC inhibitors as in vivo chemical probes - Supplement to Promote Diversity

描述(申请人提供)：黄斑性水肿症是导致美国人失明的许多主要原因，包括糖尿病、老年性黄斑变性和葡萄膜炎。目前，大量研究表明，包括血管内皮生长因子和肿瘤坏死因子在内的细胞因子表达的改变可增加血管通透性。此外，我们实验室和其他实验室的研究表明，对这些和其他通透性因子的通透性反应需要激活非典型的蛋白激酶C亚型。通过筛选商业上可用的文库，我们已经确定了这一靶点的一类抑制剂，在这项拨款中，我们建议将药物化学家、结构生物学家和细胞和分子生理学家结合起来，开发在多种眼病模型中控制视网膜血管通透性的化合物。重要的是，视网膜功能的测量将模仿临床评估。这些研究的成功完成将为非典型蛋白激酶C抑制剂治疗黄斑水肿提供强大的化学药效团、药代动力学分析、作用机制和体内有效性，并为临床试验提供特定的线索。

DESCRIPTION (provided by applicant): Macular Edema contributes to many of the leading causes of blindness in America including diabetes, age related macular degeneration and uveitis. Currently, a wide number of studies reveal that altered expression of cytokines, including vascular endothelial growth factor and tumor necrosis factor act to increase blood vessel permeability. Further, research from our laboratory, as well as others, reveals activation of atypical protein kinase C isoforms are required for the permeability response for these and other permeabilizing factors. By screening a commercially available library, we have already identified a class of inhibitors for this target and in this grant we propose to combine medicinal chemists, structural biologists and cellular and molecular physiologists to develop compounds that control retinal blood vessel permeability in multiple models of eye disease. Importantly, measures of retinal function will mimic clinical assessments. The successful completion of these studies will provide a robust chemical pharmacophore, pharmacokinetic analysis, mechanism of action and in vivo effectiveness for atypical protein kinase C inhibitors to treat macular edema with specific leads available for clinical trials.