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: 8725166
• 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
• 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/8725166
• 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

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）出现特定损失。目前的治疗方法是通过使用滴眼剂、激光治疗和/或手术来降低眼压（IOP）。尽管这种治疗可能有效，但通常不能安全地实现足够的眼压降低，有时即使眼压显着降低，视神经损伤仍然可能进展。为了补充基于 IOP 的治疗，人们正在努力开发直接保护 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内涵/RNAi 筛选方法，以确定小分子化合物和途径，其调节可以促进 RGC 的健康和存活。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可促进 RGC 存活。在本申请中，我们建议以这些发现为基础，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。目标 1 将利用 DLK 条件敲除小鼠来确定 DLK 抑制是否促进青光眼小鼠模型中的 RGC 存活。目标 2 将探索 DLK 类似物 MAP3K13 (LZK) 在 RGC 健康和生存中的可能作用。目标 3 将探讨损伤后 DLK 上调和活性的机制。由于目前可用的 DLK 抑制剂相对非特异性并且表现出显着的毒性，我们假设其中大部分是由于脱靶效应所致，因此在目标 4 中，我们采用药物化学方法来努力开发更具选择性和更安全的 DLK抑制剂。