Protein kinase inhibitors that promote RGC survival and function

描述(申请人提供)：视神经中的视网膜神经节细胞(RGC)及其轴突经常是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外伤性视神经压迫。尽管神经保护策略在治疗退行性视神经疾病方面有很大的潜力，并且已经有了重要的实验室进展，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含量的方法，并筛选各种小化合物文库，目的是寻找有希望的候选药物，以促进RGC的生存和功能。在本申请中，我们建议将重点放在一种特别有前景的化合物上。我们推测，该化合物可能通过一种新颖而有效的保护机制发挥作用，它或相关化合物可能具有补充目前治疗RGC退行性疾病的方法的潜力。这项申请提出了两个具体目标。SA1将把该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、微阵列和蛋白质组方法的互补组合，努力定义化合物发挥作用的信号机制。 公共卫生相关性：通过高含量的筛选计划，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发展成为治疗视神经疾病的新方法。在这一应用中，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有效性。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。

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.