Protein kinase inhibitors that promote RGC survival and function

描述（由申请人提供）：视神经中的视网膜神经节细胞（RGC）及其轴突经常是各种退行性疾病的靶标，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。虽然发展神经保护策略治疗退行性视神经疾病具有很大的潜力，并且已经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临床。我们和其他公司一直在追求高含量的方法，筛选各种小化合物文库，以确定有希望的候选药物，这些候选药物将促进RGC的生存和功能。在这个应用中，我们建议重点研究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有潜力补充目前治疗RGC退行性疾病的方法。此应用程序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三种啮齿类动物RGC变性和轴突再生模型。SA2将利用小鼠突变体、微阵列和蛋白质组学方法的互补组合，努力确定该化合物起作用的信号机制。

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.