The Ins2Akita mouse as a model of vision loss and neurodegeneration in diabetes
The overall goal of this research is to determine the mechanism of vision loss in diabetic retinopathy. The main objective of the proposed project is to develop functional assays of vision loss in the spontaneously diabetic Ins2Akita mouse, and compare the loss of function with assays of cell death, retinal morphomotry (cell layer thickness and nuclear counts) and synaptic protein content. A new approach that uses the optokinetic reflex will be employed to measure visual acuity and contrast sensitivity in mice. We have also established that a rapid and sensitive cell death ELISA can be used to measure apoptosis in mouse retinas. This assay measures the amount of nucleosomal fragments in the cytoplasm of cells undergoing apoptosis. Furthermore, our published data show that the content of a group of pre-synaptic proteins is depleted in the retinas of diabetic rodents, and that diabetes leads to reductionsin the thicknes of the inner retinal layers in mice and rats. These assays can be used to measure loss of function, apoptosis, retinal degeneration and synaptic malfunction in Ins2Akita diabetic mice. Therefore this project will test the general hypothesis that diabetes induces retinal neurodegeneration and compromises visual function in the Ins2Akita mouse. The first specific aim is to measure vision loss, apoptosis and retinal morphomotry in diabetic Ins2Akita mice after different durations of diabetes. The second specific aim is to measure vision loss and synaptic protein content in Ins2Akita mice, again after different durations of diabetes. It is predicted that apoptosis will be detected soon after the onset of diabetes and that visual acuity and contrast sensitivity will be correlated with loss of the retinal cell layers and with reduced synaptic protein content. This project will further establish the Ins2Akita mouse as a model of diabetic retinopathy, and will test the concept that retinal cell apoptosis and synaptic degeneration lead to vision loss. Furthermore, it will identify the threshold of synaptic protein and retinal cell loss that is required to cause a measurable loss of function in the Ins2Akita mouse.

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