Protein kinase inhibitors that promote RGC survival and function

促进 RGC 存活和功能的蛋白激酶抑制剂

基本信息

批准号：
7706852
负责人：
Donald J. Zack
金额：
$ 20.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7706852
关键词：
Affect Animal Model Anterior Ischemic Optic Neuropathy Antibodies Apoptosis Axon Biological Assay Biological Preservation Biology Brain-Derived Neurotrophic Factor CCL4 gene Cell Culture System Cell Culture Techniques Cell Death Cell Survival Cells Clinic Complement Data Degenerative Disorder Development Exons FDA approved FLT3 gene FLT3 inhibition Gastrointestinal Stromal Tumors Gene Expression Genome Glaucoma Goals Health In Vitro Knockout Mice Laboratories Lead Libraries Life Luciferases Mediating Modeling Molecular Molecular Bank Molecular Target Mutant Strains Mice Nerve Crush Neurites Neurodegenerative Disorders Neurons Neuroprotective Agents Optic Nerve Optic Nerve Injuries Optic Neuritis Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphoproteins Phosphotransferases Play Post-Translational Protein Processing Pre-Clinical Model Protein Kinase Protein Kinase Inhibitors Proteomics Rattus Receptor Protein-Tyrosine Kinases Reporting Resistance Retinal Ganglion Cells Rodent Rodent Model Role Screening procedure Signal Pathway Signal Transduction Stress Testing Therapeutic United States National Institutes of Health Vision Work axon regeneration base cell injury drug candidate excitotoxicity improved functioning in vivo injured insight interest intraperitoneal kidney cell neurite growth neuroprotection neurotrophic factor novel novel therapeutic intervention optic nerve disorder preclinical evaluation programs protein kinase inhibitor public health relevance restoration small molecule libraries transcription factor treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Retinal ganglion cells (RGC) and their axons in optic nerves are frequently targeted in a variety of degenerative disorders such as glaucoma, optic neuritis, anterior ischemic optic neuropathy, and traumatic compression of optic nerves. Although the development of neuroprotective strategies for the treatment of the degenerative optic nerve diseases has great potential, and there have been important laboratory advances, neuroprotection- based treatment approaches have not yet made it to the clinic. We, and others, have been pursuing a high content approach and screening various libraries of small compounds with the goal of identifying promising drug candidates that would promote RGC survival and function. In this application, we propose to focus on one particularly promising compound. We hypothesize that the compound may act through a novel and potent protective mechanism and that it, or related compounds, may have the potential to complement present approaches for the treatment of RGC degenerative diseases. This application proposes two Specific Aims. SA1 will extend the preclinical evaluation of the compound to three rodent models of RGC degeneration and axon regeneration. SA2 will use a complementary combination of mouse mutants, microarrays, and proteomic approaches in an effort to define the signaling mechanisms by which the compound acts. PUBLIC HEALTH RELEVANCE: Through a high content screening program we have identified molecules that promote the survival and health of retinal ganglion cells, the cells that are injured and die in glaucoma and other optic nerve diseases. These molecules, and related ones, have the potential to be developed into new treatment approaches for the optic nerve diseases. In this application, we propose testing these molecules to determine their efficacy in animal models for retinal ganglion cell injury. We also propose to explore the mechanisms by which these molecules work, with the hope that this will contribute to the development of new treatment strategies for glaucoma and other optic nerve diseases.

描述（由申请人提供）：视网膜神经节细胞（RGC）及其轴突在视神经中经常针对多种退行性疾病，例如青光眼，视神经炎，前缺血性神经性神经病，以及光神经的创伤性压缩。尽管开发神经保护策略以治疗退化性视神经疾病具有很大的潜力，并且有重要的实验室进展，但基于神经保护的治疗方法尚未进入诊所。我们和其他人一直在采用高素质的方法，并筛选各种小型化合物的文库，目的是确定有前途的候选药物，这些候选者将促进RGC的生存和功能。在此应用程序中，我们建议专注于一种特别有希望的化合物。我们假设该化合物可以通过一种新颖而有效的保护机制作用，并且它或相关化合物可能具有补充当前治疗RGC退行性疾病的方法。该应用程序提出了两个具体目标。 SA1将将化合物的临床前评估扩展到RGC变性和轴突再生的三种啮齿动物模型。 SA2将使用小鼠突变体，微阵列和蛋白质组学方法的互补组合，以定义化合物作用的信号传导机制。公共卫生相关性：通过高素质筛选计划，我们确定了促进视网膜神经节细胞的生存和健康的分子，受伤并死亡的细胞在青光眼和其他视神经疾病中。这些分子及相关分子有可能发展为视神经疾病的新治疗方法。在此应用中，我们建议对这些分子进行测试，以确定它们在视网膜神经节细胞损伤的动物模型中的功效。我们还建议探索这些分子起作用的机制，希望这将有助于制定青光眼和其他视神经疾病的新治疗策略。