MMPC :: MICROMouse Program Application Abstract

MICROMouse Program Application Abstract

MMPC Funded Abstracts

MICROMouse

Funding Programs

Phenotyping Visual Cycle Dysfunction in Diabetic Retinopathy

Bruce Berkowitz (Detroit, MI)

MICROMouse Program

Healthy vision requires a continuous supply of 11-cis-retinal for rhodopsin regeneration via the visual cycle, and for photoreceptor membrane depolarization via open cyclic guanosine monophosphate-gated ion channels. Chronically impaired visual cycle function, an important disease phenotype linked with retinal and visual lesions, can be analytically and non-invasively evaluated in vivo using manganese-enhanced MRI (MEMRI). During our prior MMPC Pilot and Feasibility grant periods, we found evidence for a visual cycle lesion before the appearance of microvascular histopathology: in dark adapted diabetic mice, photoreceptor ion channels were abnormally closed on MEMRI and visual performance was impaired on optokinetic tracking (OKT) examination. Notably, acute, systemic 11-cis-retinal treatment restored outer retinal channel opening and contrast sensitivity, confirming a critical contribution of visual cycle dysfunction. However, the beneficial effect was partial: outer retinal activity and contrast sensitivity were not restored to control levels, and inner retinal dysfunction or visual acuity were not affected by the treatment. We had previously reported that chronic (i.e., preventative) therapy of a non-visual cycle specific target inhibited diabetic-induced vascular lesions and corrected the preceding inner and outer neuroretinal dysfunction. We reason that chronic correction will be a better test than acute therapy for a diabetes-evoked visual cycle dysfunction and its consequences. Our central hypothesis is that in diabetic mice chronic treatment of visual cycle dysfunction will a) correct inner and outer neuroretinal dysfunction, b) inhibit microvascular lesion formation, and c) improve visual performance, and thus provide an improved test of this diabetes-evoked pathophenotype. The overall objective of this proposal is to develop and apply a powerful evaluation paradigm to meet a newly identified and important diabetes-induced phenotyping need in a mouse model. Our rationale is that testing the mechanisms underlying important disease phenotypes of diabetic retinal disease will facilitate the development of new pharmacological approaches for its treatment. A major positive impact of these studies will be the identification of a novel approach to characterize fundamental sight-threatening abnormalities linked with diabetes. The following specific aim will address our central hypothesis: Aim: Test the hypothesis that diabetes induces a chronic visual cycle lesion that critically contributes to inner and outer neuroretinal dysfunction, retinal vessel histopathology, and visual performance impairment. 2, 5, and 9 mo diabetic dark adapted C57Bl/6 mice, and age-matched non-diabetic wild type mice with and without oral 9-cis-retinyl acetate supplementation will be studied. Long-term oral administration of 9-cis-retinyl acetate, a prodrug currently undergoing clinical trial evaluation, significantly improves photoreceptor function in non-diabetic mouse models. At each time point, we will objectively compare the degree of inner and outer retinal ion channel activity (MEMRI), visual performance (OKT), the concentration of visual cycle intermediates (biochemistry), and retinal vascular histopathology. Our hypothesis predicts that chronic 9-cis-retinyl acetate treatment will significantly benefit all outcome measures. This competing renewal is responsive to the Pilot & Feasibility Program part of the MICROMouse Program by using a combination of MEMRI (to evaluate visual cycle dysfunction in vivo) and 9-cis-retinyl acetate (a clinically relevant challenge that chronically alleviates dysfunctional visual cycle) to address an identifiable, outstanding phenotyping need involving inner and outer retinal and visual lesions induced by diabetes in a mouse model

Menu

Newsletter