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: 7934529
• 负责人: Donald J. Zack
• 金额: $ 24.35万
• 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 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934529
• 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）及其轴突经常成为多种退行性疾病的靶标，例如青光眼、视神经炎、前部缺血性视神经病变和视神经外伤性压迫。尽管开发治疗退行性视神经疾病的神经保护策略具有巨大潜力，并且实验室取得了重要进展，但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内涵方法并筛选各种小化合物库，目的是识别有前途的候选药物，以促进 RGC 的存活和功能。在此应用中，我们建议重点关注一种特别有前途的化合物。我们假设该化合物可能通过一种新颖且有效的保护机制发挥作用，并且它或相关化合物可能有潜力补充目前治疗 RGC 退行性疾病的方法。本申请提出了两个具体目标。 SA1 将该化合物的临床前评估扩展到三种 RGC 变性和轴突再生的啮齿动物模型。 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来努力定义该化合物发挥作用的信号传导机制。 公共健康相关性：通过高内容筛选计划，我们已经确定了促进视网膜神经节细胞（在青光眼和其他视神经疾病中受伤和死亡的细胞）存活和健康的分子。这些分子和相关分子有可能被开发成视神经疾病的新治疗方法。在此应用中，我们建议测试这些分子以确定它们在视网膜神经节细胞损伤动物模型中的功效。我们还建议探索这些分子的作用机制，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。