In this application the candidate proposes to explore age-related retinal atrophy and dysfunction. The proposed studies are based on the observation that age-related retinal atrophy is accompanied by the degeneration of photoreceptor cells and the loss of excitatory synaptic input from the photoreceptor cells to the bipolar and horizontal cells and the hypothesis that this loss of function is related to changes in the expression of any or several of the numerous receptor isoforms that receive and process the signals transmitted by the photoreceptor cells of the outermost retinal layer via glutamate. The proposed mechanism rests on evidence that in vertebrate retina, release of glut in the dark de-polarizes OFF-bipolar cells and hyper-polarizes ON-bipolar cells. Because all rod bipolar cells are hyperpolarized in the dark, an age-related loss of glutamate releasing PR cells would attenuate glut at the OFF-bipolar and to sustained depolarization in the dark (as it occurs in response to light). This could lead to increased intracellular Ca2+ and the overexpression of immediate-response genes, eg heat shock proteins, which ultimately may result in alterations in the encoding of different subunits of the glutamate receptors. This in some instances has been interpreted as inducing excitotoxic cell damage.
The Specific aims i nclude: 1. The characterization of various glutamate receptor subunits (isoforms) in retinal neurons and glial cells from young vs old rat retinae, 2. Chracterization of Gl. R component expression in human retinal tissues at different age-levels, and 3. The expression and distribution of constitutive and inducible heat shock roteins HSC 70 and HSP 70 in neuron and glial or Mueller cells, as markers of metabolic stress in aging.
| Grigorenko, E; Glazier, S; Bell, W et al. (1997) Changes in glutamate receptor subunit composition in hippocampus and cortex in patients with refractory epilepsy. J Neurol Sci 153:35-45 |
