Retinal ganglion cell (RGC) death is the primary cause of irreversible blindness in Open Angle Glaucoma (OAG) and most optic neuropathies. The goal of this project is to prevent blindness in these diseases by obtaining the information needed to understand the etiology of RGC vulnerability, and use this understanding to develop approaches that prevent cell death. Our objective is determining RGC susceptibility to stressors such as IOP elevation, metabolic load, and neurotrophic factor (NT) deficiency in mouse models of glaucoma and optic neuropathy during the stage of progressive RGC dysfunction preceding death (critical period). Our central hypothesis is that RGC death is the result of failure of autoregulatory/adaptive processes that can no longer sustain normal RGC homeostasis, resulting in loss of RGC electrical responsiveness. During the critical period, RGC responsiveness is modifiable (plastic) upon stressors such as IOP, metabolic demand and NT support, thus providing a rationale and a target for therapeutic intervention. Using innovative methods, we will acutely modulate the levels of these stressors and simultaneously assess modifiability of RGC electrical responsiveness over time using pattern electroretinogram (PERG) and visual evoked potential (VEP). We will also use state-of-the-art optical coherence tomography (OCT) to serially monitor thickness of inner retinal layers, as well as retinal immunohistochemistry at endpoint. We will attain our goal and objective by accomplishing the following aims: 1) Test the hypothesis that RGC plasticity occurs in a specific time window in mouse models of glaucoma and optic neuropathy. Models will be the Myoc transgenic mouse of glaucoma, the ND4 transgenic mouse of multiple sclerosis, and the MOG-specific TCR transgenic mouse of optic neuritis. Controls will be corresponding non-pathological congenic mice. We will non-invasively alter either IOP with changes of body posture, or the metabolic demand with flickering light, and will measure corresponding changes of the PERG/VEP signal that precede loss of OCT signal;2) Test the hypothesis that RGC plasticity is inducible in mouse models of chronic NT deficiency. We will perform unilateral lesions of the superior colliculus (SC) in C57BL/6J and DBA/2J mice and will quantify changes of the PERG and OCT signal in each eye. We will also induce IOP and metabolic stress in SC-lesioned mice to quantify acquired susceptibility of the PERG signal. Successful completion of our research will establish a new conceptual model of RGC susceptibility, and will improve our technical capability of detecting diseases'onset, monitoring their progression and the effect of treatment, eventually changing clinical practice. This will represent a significant advancement in the field and will be influential on future research on glaucoma and other neurodegenerative diseases involving RGC.
Glaucoma and optic neuropathies are leading causes of irreversible blindness, whose common cause is retinal ganglion cell (RGC) death. In this project we investigate the hypothesis that RGC dysfunction and demise is initiated by failure of autoregulatory processes that can no longer sustain normal homeostasis, resulting in progressive loss of pattern electroretinogram and susceptibility to stressors such as IOP elevation, increased metabolic demand, and neurotrophic factors deficiency. Understanding the etiology of RGC vulnerability is a necessary step to develop therapeutic approaches that reduce or eliminate its effects on cell death.
|Chou, Tsung-Han; Feuer, William J; Schwartz, Odelia et al. (2016) Integrative properties of retinal ganglion cell electrical responsiveness depend on neurotrophic support and genotype in the mouse. Exp Eye Res 145:68-74|
|Porciatti, Vittorio (2015) Electrophysiological assessment of retinal ganglion cell function. Exp Eye Res 141:164-70|
|Talla, Venu; Koilkonda, Rajeshwari; Porciatti, Vittorio et al. (2015) Complex I subunit gene therapy with NDUFA6 ameliorates neurodegeneration in EAE. Invest Ophthalmol Vis Sci 56:1129-40|
|Koilkonda, Rajeshwari; Yu, Hong; Talla, Venu et al. (2014) LHON gene therapy vector prevents visual loss and optic neuropathy induced by G11778A mutant mitochondrial DNA: biodistribution and toxicology profile. Invest Ophthalmol Vis Sci 55:7739-53|
|Chou, Tsung-Han; Bohorquez, Jorge; Toft-Nielsen, Jonathon et al. (2014) Robust mouse pattern electroretinograms derived simultaneously from each eye using a common snout electrode. Invest Ophthalmol Vis Sci 55:2469-75|
|Chou, Tsung-Han; Tomarev, Stanislav; Porciatti, Vittorio (2014) Transgenic mice expressing mutated Tyr437His human myocilin develop progressive loss of retinal ganglion cell electrical responsiveness and axonopathy with normal iop. Invest Ophthalmol Vis Sci 55:5602-9|
|Porciatti, Vittorio; Bosse, Brandon; Parekh, Prashant K et al. (2014) Adaptation of the steady-state PERG in early glaucoma. J Glaucoma 23:494-500|
|Ã–zdamar, Ã–zcan; Toft-Nielsen, Jonathon; BohÃ³rquez, Jorge et al. (2014) Relationship between transient and steady-state pattern electroretinograms: theoretical and experimental assessment. Invest Ophthalmol Vis Sci 55:8560-70|
|Talla, Venu; Porciatti, Vittorio; Chiodo, Vince et al. (2014) Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis. Invest Ophthalmol Vis Sci 55:5214-26|
|Guy, John; Feuer, William J; Porciatti, Vittorio et al. (2014) Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 55:841-8|
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