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

• 批准号: 8573119
• 负责人: Donald J. Zack
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573119
• 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; public health relevance; research clinical testing; response; response to injury; screening; small molecule; therapeutic target

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.

项目概要 青光眼是一种神经退行性疾病，其中视网膜出现特定损失 神经节细胞（RGC）。目前的治疗旨在降低眼压 (IOP) 通过使用滴眼剂、激光治疗和/或手术治疗。 尽管这种治疗可能有效，但通常不能充分降低眼压 可以安全地实现，有时即使眼压显着降低，仍然存在 可能是视神经损伤的进展。努力补充基于 IOP 的 疗法，已努力开发神经保护疗法 直接采取行动以维护 RGC 的健康和功能。然而，尽管重要 实验室进展，基于神经保护的青光眼治疗方法 尚未到达诊所。为了帮助推进临床 可行的神经保护策略，我们一直在追求综合的高 内容/RNAi筛选方法来鉴定小分子化合物和 其调节可以促进 RGC 健康和生存的途径。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点，并已表明其在体外的抑制作用 并在体内促进 RGC 存活。在此应用程序中，我们建议建立在 这些发现有助于开发安全有效的药物 用于治疗青光眼和其他形式视神经疾病的神经保护药物 神经病变。目标 1 将利用 DLK 条件敲除小鼠来确定 DLK 抑制是否会促进青光眼小鼠模型中 RGC 的存活。 目标 2 将探索 DLK 类似物 MAP3K13 (LZK) 在 RGC 中的可能作用 健康和生存。目标3将探索DLK上调的机制和 受伤后的活动。因为目前可用的DLK抑制剂相对 非特异性并表现出显着的毒性，我们假设其中大部分是 由于脱靶效应，在目标 4 中，我们采用药物化学方法 致力于开发更具选择性和更安全的 DLK 抑制剂。