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

描述(申请人提供)：青光眼是一种神经退行性疾病，有视网膜神经节细胞(RGC)的特异性丢失。目前的治疗是通过使用眼药水、激光治疗和/或手术来降低眼压(IOP)。虽然这种治疗方法可以有效，但通常不能安全地达到足够的眼压降低，有时即使显著降低眼压，视神经损伤仍可能进展。为了补充基于眼压的治疗，已经努力开发神经保护疗法，直接作用于保护RGC的健康和功能。然而，尽管取得了重要的实验室进展，基于神经保护的青光眼治疗方法尚未进入临床。为了促进临床上可行的神经保护策略，我们一直在寻求一种高含量/RNAi相结合的筛选方法，以确定其调节可以促进RGC健康和存活的小分子化合物和通路。通过这项工作，我们发现双亮氨酸拉链激酶(DLK，MAP3K12)是一个有吸引力的治疗靶点，并表明其在体外和体内的抑制都能促进RGC的存活。在这项应用中，我们建议以这些发现为基础，朝着开发一种安全有效的神经保护药物的方向发展，用于治疗青光眼和其他形式的视神经疾病。目的1将利用DLK条件基因敲除小鼠来确定DLK抑制是否促进青光眼小鼠模型的RGC存活。目的2将探讨DLK类似物MAP3K13(LZK)在RGC健康和生存中的可能作用。目的3探讨损伤后DLK上调和活动的机制。由于目前可用的DLK抑制剂是相对非特异性的，并显示出显著的毒性，我们假设其中大部分是由于靶外效应，目标4是因为我们采用药物化学方法努力开发更具选择性和更安全的DLK抑制剂。

DESCRIPTION (provided by applicant): 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.