Retinal ganglion cells (RGC) and their axons in optic nerves are frequently targeted in a variety of degenerative disorders such as glaucoma, optic neuritis, anterior ischemic optic neuropathy, and traumatic compression of optic nerves. Although the development of neuroprotective strategies for the treatment of the degenerative optic nerve diseases has great potential, and there have been important laboratory advances, neuroprotection- based treatment approaches have not yet made it to the clinic. We, and others, have been pursuing a high content approach and screening various libraries of small compounds with the goal of identifying promising drug candidates that would promote RGC survival and function. In this application, we propose to focus on one particularly promising compound. We hypothesize that the compound may act through a novel and potent protective mechanism and that it, or related compounds, may have the potential to complement present approaches for the treatment of RGC degenerative diseases. This application proposes two Specific Aims. SA1 will extend the preclinical evaluation of the compound to three rodent models of RGC degeneration and axon regeneration. SA2 will use a complementary combination of mouse mutants, microarrays, and proteomic approaches in an effort to define the signaling mechanisms by which the compound acts.
Through a high content screening program we have identified molecules that promote the survival and health of retinal ganglion cells, the cells that are injured and die in glaucoma and other optic nerve diseases. These molecules, and related ones, have the potential to be developed into new treatment approaches for the optic nerve diseases. In this application, we propose testing these molecules to determine their efficacy in animal models for retinal ganglion cell injury. We also propose to explore the mechanisms by which these molecules work, with the hope that this will contribute to the development of new treatment strategies for glaucoma and other optic nerve diseases.
| Sluch, Valentin M; Zack, Donald J (2014) Stem cells, retinal ganglion cells and glaucoma. Dev Ophthalmol 53:111-21 |
| Berlinicke, Cynthia A; Ackermann, Christopher F; Chen, Steve H et al. (2012) High-content screening data management for drug discovery in a small- to medium-size laboratory: results of a collaborative pilot study focused on user expectations as indicators of effectiveness. J Lab Autom 17:255-65 |
| Hackler Jr, Laszlo; Masuda, Tomohiro; Oliver, Verity F et al. (2012) Use of laser capture microdissection for analysis of retinal mRNA/miRNA expression and DNA methylation. Methods Mol Biol 884:289-304 |
| Nguyen, Judy V; Soto, Ileana; Kim, Keun-Young et al. (2011) Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proc Natl Acad Sci U S A 108:1176-81 |
