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

基本信息

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
项目类别：
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

项目摘要

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）：黄斑水肿有助于美国的许多主要原因，包括糖尿病，与年龄相关的黄斑变性和葡萄膜炎。目前，许多研究表明，细胞因子的表达改变，包括血管内皮生长因子和肿瘤坏死因子可提高血管渗透性。此外，我们实验室以及其他的研究揭示了这些和其他通透性因子的渗透性响应需要非典型蛋白激酶C同工型的激活。通过筛选市售的文库，我们已经确定了该目标的一类抑制剂，在这项赠款中，我们建议将药物化学家，结构生物学家以及细胞和分子生理学家结合起来，以开发多种模型中的视网膜血管渗透性的化合物。重要的是，视网膜功能的度量将模仿临床评估。这些研究的成功完成将为非典型蛋白激酶C抑制剂提供强大的化学药效团，药代动力学分析，作用机理和体内有效性，可通过可用于临床试验的特定铅来治疗黄斑水肿。