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

发现新型非典型 PKC 抑制剂作为体内化学探针 - 促进多样性的补充

• 批准号: 9196555
• 负责人: David Antonetti
• 金额: $ 1.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196555
• 关键词: Age related macular degeneration; Americas; Amino Acids; Animal Model; Antibodies; Area; Biological Assay; Blindness; Blood Vessels; Cell Culture Techniques; Chemicals; Clinical; Clinical Trials; Clinical assessments; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Drug Kinetics; Edema; Effectiveness; Endophthalmitis; Extravasation; Eye diseases; Figs - dietary; Fluorescein Angiography; Funding Opportunities; Goals; Grant; Growth Factor Gene; Health; In Vitro; Inflammatory; Injection of therapeutic agent; Intervention Trial; KDR gene; Kinetics; Laboratories; Lead; Libraries; Macular degeneration; Measures; Metabolic; Modeling; Molecular; Molecular Conformation; Operative Surgical Procedures; Optical Coherence Tomography; Outcome; PDPK1 gene; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Prevention trial; Property; Protein Isoforms; Protein Kinase C Inhibitor; Public Health; Publications; Regulation; Research; Retina; Retinal; Retinal Edemas; Retinal Vein Occlusion; Site; Structural Biologist; Structure; Structure-Activity Relationship; TNF gene; Testing; Therapeutic; Toxic effect; Tumor Necrosis Factor Receptor; United States; Uveitis; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vertebral column; Vision; atypical protein kinase C; base; central retinal vein occlusion; cytokine; in vivo; inhibitor/antagonist; intraperitoneal; macular edema; novel; novel therapeutics; pharmacophore; polypeptide; prevent; research clinical testing; research study; response; retina blood vessel structure; screening; small molecule; small molecule libraries; therapeutic effectiveness

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.

描述（由申请人提供）：黄斑水肿导致美国许多主要致盲原因，包括糖尿病、年龄相关性黄斑变性和葡萄膜炎。目前，大量的研究表明，细胞因子，包括血管内皮生长因子和肿瘤坏死因子的表达改变，以增加血管通透性。此外，我们实验室的研究以及其他研究表明，非典型蛋白激酶C亚型的激活是这些和其他透化因子的渗透性响应所必需的。通过筛选商业上可获得的库，我们已经确定了这一目标的一类抑制剂，并在此授予我们建议联合收割机药物化学家，结构生物学家和细胞和分子生理学家开发化合物，控制视网膜血管通透性在多种模型的眼病。重要的是，视网膜功能的测量将模拟临床评估。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，并提供可用于临床试验的特定线索。