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

双亮氨酸拉链激酶 (DLK) 作为视网膜神经节细胞损伤的调节剂

基本信息

批准号：
8925084
负责人：
Donald J. Zack
金额：
$ 39.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925084
关键词：
Adverse effects Animal Model Animals Behavior Biological Assay Blindness Cell Culture Techniques Cell Death Cell Survival Cells Chronic Clinic Clinical Collaborations Complement Development Dose Elements Exhibits Eye Eyedrops Glaucoma Health Human Human Pathology In Vitro Injury Knock-out Knockout Mice Laboratories Lasers Lead Leucine Zippers Libraries MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Medical Messenger RNA Modeling Molecular Probes Mus N-Methylaspartate Nerve Crush Neurodegenerative Disorders Neuroprotective Agents Operative Surgical Procedures Optic Nerve Optic Nerve Transections Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Physiologic Intraocular Pressure Play Protein Kinase Protein Kinase Inhibitors RNA RNA Interference Rattus Regulation Retinal Ganglion Cells Role Safety Sampling Secondary to Signal Transduction Small Interfering RNA Sutent Testing Toxic effect Transcript Translational Research Up-Regulation Visual Work analog base cell injury disability established cell line human disease improved in vitro Assay in vivo in vivo Model inhibitor/antagonist injured kinase inhibitor knock-down mouse model neuroprotection neurotrophic factor novel optic nerve disorder pressure programs protein expression protein kinase inhibitor research clinical testing response response to injury screening small molecule therapeutic target

项目摘要

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.

描述（由申请人提供）：青光眼是一种神经退行性疾病，其中视网膜神经节细胞（RGC）的特异性丧失。当前管理通过使用眼滴，激光治疗和/或手术手术来降低眼压（IOP）。尽管这种治疗方法可能是有效的，但通常无法安全地实现足够的IOP降低，有时即使降低显着降低，仍然可能是视神经损伤的进展。为了补充基于IOP的疗法，已经努力开发直接起作用RGC健康和功能的神经保护疗法。然而，尽管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诊所。为了帮助迈向临床上可行的神经保护策略，我们一直在追求一种综合的高含量/RNAi筛选方法，以识别可以调节可以促进RGC健康和生存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，MAP3K12）是一个有吸引力的治疗靶标，并且表明其在体外和体内都可以促进RGC的存活率。在此应用中，我们建议以这些发现为基础，以发展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。 AIM 1将利用DLK条件基因敲除小鼠来确定DLK抑制是否促进了青光眼小鼠模型中的RGC存活。 AIM 2将探讨DLK类似物，MAP3K13（LZK）在RGC健康和生存中的可能作用。 AIM 3将探索受伤后DLK上调和活动的机制。由于目前可用的DLK抑制剂相对非特异性，并且显示出明显的毒性，因此我们假设这是由于脱靶效应所致，因此在AIM 4中，我们采用药物化学方法来开发更具选择性和更安全的DLK抑制剂。