Preserving the Precious Gift of Sight

Paul Shin-Hyun Park, PhD

 

BASIC RESEARCH PROJECT

Dept. of Ophthalmology and Visual Sciences

Case Western Reserve University

Cleveland, OH

Dr. Park’s Research Project

A potential neuroprotective role for GPR75 in the retina
 

Current Research Interests

The retina is exposed to a variety of stresses during normal function, which can lead to retinal degeneration in the absence of neuroprotective mechanisms. In diseased states, these neuroprotective mechanisms may become overwhelmed or may be the source of dysfunction themselves. In this proposal, the possibility that GPR75 can serve as a neuroprotective target in the retina is explored. Defects in this protein may contribute to retinal degeneration occurring in diseases such as age-related macular degeneration. There are currently only 5 PubMed publications reporting on studies conducted on this receptor. Despite the scarcity of information on GPR75, current studies highlight the potential of this receptor to exhibit neuroprotective properties.

Progress in 2016

Dr. Park continued his examination of the retina of GPR75 knockout (GPR75-/-) mice. The number of nuclei in the outer nuclear layer, which represents the nuclei of photoreceptor cells, were quantified in those regions and the data plotted. The outer nuclear layer in 8-month old GPR75-/- mice exhibited a less compact structure and appeared to contain fewer rows of nuclei than in either 3 or 6-month old mice. No significant differences were observed in the outer and inner segments of photoreceptor cells at any age tested. These studies suggest that in the absence of GPR75, the retina is more susceptible to environmental stresses with age, possibly due to light damage over time. Characterization of GPR75 mutants detected in patients with age-related macular degeneration suggest that some of the mutants exhibit a structural deficit, which is consistent with the notion that defects in GPR75 can contribute to the pathogenesis of AMD.

Plans for 2017

Aim 1) Testing for neuroprotective properties in retinal cells. Studies will test whether GPR75 in retinal photoreceptor cells can protect against stress-induced retinal cell death similar to that found in age-related macular degeneration and other retinal degenerative disorders. Aim 2) Testing for neuroprotective properties in a mouse model – A GPR75 knockout mouse recently obtained will be characterized. If GPR75 does play a neuroprotective role in the retina, this mouse model will provide a novel tool to study the pathogenesis of AMD and allow testing of pharmacological compounds. Aim 3) Determining the consequences of mutations in GPR75 – Five putative pathogenic mutations in the coding sequence of the GPR75 gene have been found in patients with AMD and not in control subjects. These mutants will be characterized to determine the functional and structural perturbations in the receptor molecule and cellular consequences caused by the mutations. These studies will provide insights into how defects in the GPR75 receptor molecule may potentiate or lead to AMD and may highlight novel therapeutic strategies to alleviate detrimental effects.

Progress in 2015

Aim 1) Testing for neuroprotective properties in retinal cells.

Aim 2) Testing for neuroprotective properties in a mouse model – A GPR75 knockout mouse recently obtained will be characterized. If GPR75 does play a neuroprotective role in the retina, this mouse model will provide a novel tool to study the pathogenesis of AMD and allow testing of pharmacological compounds.

Aim 3) Determining the consequences of mutations in GPR75 – Five putative pathogenic mutations in the coding sequence of the GPR75 gene have been found in patients with AMD and not in control subjects. These mutants will be characterized to determine the functional and structural perturbations in the receptor molecule and cellular consequences caused by the mutations.

1) Dr. Park demonstrated that GPR75 appears to protect 661W photoreceptor cells against the toxic effects induced by light, thereby supporting the hypothesis that GPR75 has a neuroprotective role in the retina. 2) He examined histology of retina from GPR75-/- mice at 6 months of age, and the retina showed no remarkable findings. Older mice must be examined. 3) He developed stable cell lines expressing each of the GPR75 forms. These will be used in future pharmacology studies.

 
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Mission of RRF

The mission of the Retina Research Foundation is to reduce retinal blindness worldwide by funding programs in research and education. As a public charity, RRF raises funds from the private sector and the investment of its endowment funds.

RRF’s 48th Anniversary

October 1, 2017