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.

项目总结