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.
Through high content and siRNA screening programs we have identified the protein kinase DLK as playing an important role in RGC death following injury. Inhibition of DLK provides a potential mechanism to promote RGC survival in glaucoma and in other forms of optic nerve disease. In this application, we propose to determine the ability of DLK inhibition to promote RGC survival in an animal model of glaucoma, study the mechanism of DLK regulation and action, and develop more selective DLK inhibitors.
|Fernandes, Kimberly A; Mitchell, Katherine L; Patel, Amit et al. (2018) Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Exp Eye Res 171:54-61|
|Welsbie, Derek S; Mitchell, Katherine L; Jaskula-Ranga, Vinod et al. (2017) Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons. Neuron 94:1142-1154.e6|
|Antony, Bhavna J; Carass, Aaron; Lang, Andrew et al. (2017) Longitudinal Analysis of Mouse SDOCT Volumes. Proc SPIE Int Soc Opt Eng 10137:|
|Levin, Leonard A; Miller, Joan W; Zack, Donald J et al. (2017) Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative. Ophthalmology 124:926-934|
|Chamling, Xitiz; Sluch, Valentin M; Zack, Donald J (2016) The Potential of Human Stem Cells for the Study and Treatment of Glaucoma. Invest Ophthalmol Vis Sci 57:ORSFi1-6|
|Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas et al. (2016) A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium. Invest Ophthalmol Vis Sci 57:3974-81|
|Bailey, Jessica N Cooke; Loomis, Stephanie J; Kang, Jae H et al. (2016) Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet 48:189-94|
|Ouyang, Hong; Goldberg, Jeffrey L; Chen, Shuyi et al. (2016) Ocular Stem Cell Research from Basic Science to Clinical Application: A Report from Zhongshan Ophthalmic Center Ocular Stem Cell Symposium. Int J Mol Sci 17:415|
|Sluch, Valentin M; Davis, Chung-ha O; Ranganathan, Vinod et al. (2015) Differentiation of human ESCs to retinal ganglion cells using a CRISPR engineered reporter cell line. Sci Rep 5:16595|
|Springelkamp, Henriët; Mishra, Aniket; Hysi, Pirro G et al. (2015) Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology. Genet Epidemiol 39:207-16|
Showing the most recent 10 out of 13 publications