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

描述（由申请人提供）：青光眼是一种神经退行性疾病，其中存在视网膜神经节细胞（RGC）的特异性损失。目前的管理是针对降低眼压（IOP），通过使用滴眼液，激光治疗，和/或手术。虽然这种治疗可能是有效的，但通常不能安全地实现足够的IOP降低，有时即使IOP显著降低，仍可能存在视神经损伤的进展。为了补充基于IOP的治疗，已经努力开发直接用于保持RGC健康和功能的神经保护疗法。然而，尽管实验室取得了重要进展，但基于神经保护的青光眼治疗方法尚未进入临床。为了帮助推进临床上可行的神经保护策略，我们一直在寻求一种组合的高含量/RNAi筛选方法，以鉴定其调节可以促进RGC健康和存活的小分子化合物和途径。通过这项工作，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，并且已经表明其在体外和体内的抑制促进RGC存活。在本申请中，我们建议在这些发现的基础上开发一种安全有效的神经保护药物，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将探索DLK类似物MAP 3 K13（LZK）在RGC健康和存活中的可能作用。目的3探讨损伤后DLK表达上调及其活性变化的机制。由于目前可用的DLK抑制剂相对非特异性并显示出显著的毒性，我们假设其中大部分是由于脱靶效应，因此在目标4中，我们采取药物化学方法以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.