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

• 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
• 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

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）：视神经中的视网膜神经节细胞（RGC）及其轴突经常成为各种退行性疾病的靶点，如青光眼、视神经炎、前部缺血性视神经病变和视神经的创伤性压迫。尽管用于治疗退行性视神经疾病的神经保护策略的开发具有巨大的潜力，并且已经有重要的实验室进展，但是基于神经保护的治疗方法尚未进入临床。我们和其他人一直在追求高含量的方法，并筛选各种小化合物库，目的是确定有前途的候选药物，以促进RGC的生存和功能。在本申请中，我们建议集中在一个特别有前途的化合物。我们假设该化合物可能通过一种新的有效的保护机制起作用，并且它或相关化合物可能具有补充目前用于治疗RGC退行性疾病的方法的潜力。本申请提出了两个具体目标。SA1将该化合物的临床前评价扩展到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，以确定化合物作用的信号传导机制。 公共卫生相关性：通过高含量的筛选程序，我们已经确定了促进视网膜神经节细胞存活和健康的分子，这些细胞在青光眼和其他视神经疾病中受伤和死亡。这些分子及其相关分子有可能成为治疗视神经疾病的新方法。在本申请中，我们提出测试这些分子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的工作机制，希望这将有助于开发青光眼和其他视神经疾病的新治疗策略。