Dual Leucine Zipper Kinase (DLK) as a Mediator of Retinal Ganglion Cell Injury

项目摘要 青光眼是一种神经退行性疾病，其中存在特定的视网膜色素变性。 神经节细胞（RGCs）。目前的管理是针对降低眼压 (IOP)通过使用眼药水、激光治疗和/或手术。 虽然这种治疗可能是有效的，但通常不能充分降低IOP 可以安全地实现，有时即使IOP显着降低，仍然存在 可能是视神经损伤的进展为了补充基于IOP的 在神经保护疗法中，已经努力开发神经保护疗法， 直接采取行动，以维持研资局的健康及运作。尽管重要 实验室进展，基于神经保护的青光眼治疗方法 还没到诊所为了帮助推进临床 可行的神经保护策略，我们一直在寻求一种联合的高 内容/RNAi筛选方法来鉴定小分子化合物， 这些通路的调节可以促进RGC的健康和存活。通过 这项工作中，我们发现双亮氨酸拉链激酶（DLK，MAP 3 K12））是 一个有吸引力的治疗靶点，并已表明，它的抑制，无论是在体外 并且在体内促进RGC存活。在本申请中，我们建议建立在 这些发现将推动开发安全有效的 用于治疗青光眼和其他形式的视神经损害的神经保护药物 神经疾病Aim 1将利用DLK条件性敲除小鼠来确定 DLK抑制是否促进青光眼小鼠模型中RGC的存活。 目的2：探讨DLK类似物MAP 3 K13（LZK）在RGC中的可能作用 健康和生存。目的3探讨DLK上调的机制， 受伤后的活动。由于目前可用的DLK抑制剂相对 非特异性的，并显示出显着的毒性，其中大部分我们假设是 由于脱靶效应，在目标4中，我们采用药物化学方法， 努力开发更有选择性和更安全的DLK抑制剂。

Project Summary Glaucoma is a neurodegenerative disease in which there is specific loss of retinal ganglion cells (RGCs). Current management is directed at lowering eye pressure (IOP) through the use of eye drops, laser treatment, and/or operative surgery. Although such treatment can be effective, often sufficient IOP lowering can not be safely achieved, and sometimes even with significant IOP lowering there still can be progression of optic nerve damage. In an effort to complement IOP-based therapy, efforts have been made to develop neuroprotective therapies that directly act to preserve RGC health and function. However, despite important laboratory advances, neuroprotection-based treatment approaches for glaucoma have not yet made it to the clinic. In order to help advance toward a clinically viable neuroprotective strategy, we have been pursuing a combined high content/RNAi screening approach to identify small molecule compounds and pathways whose modulation that can promote RGC health and survival. Through this work we have found that the dual leucine zipper kinase (DLK, MAP3K12)) is an attractive therapeutic target, and have shown that its inhibition both in vitro and in vivo promotes RGC survival. In this application, we propose to build upon these findings to move towards development of a safe and efficacious neuroprotective drug for the treatment of glaucoma and other forms of optic nerve disease. Aim 1 will utilize a DLK conditional knockout mouse to determine whether DLK inhibition promotes RGC survival in a mouse model of glaucoma. Aim 2 will explore the possible role of a DLK analog, MAP3K13 (LZK) in RGC health and survival. Aim 3 will explore the mechanism of DLK upregulation and activity following injury. Because currently available DLK inhibitors are relatively non-specific and show significant toxicity, much of which we hypothesize to be due to off-target effects, in Aim 4 for we take a medicinal chemistry approach in an effort to develop a more selective and safer DLK inhibitor.