Retinitis pigmentosa (RP) represents a major cause of visual loss in the United States. The primary focus of this grant has been on physiological mechanisms of rod loss in children and young adults. Two critical developments over the past grant period have influenced the direction of this renewal. One is the identification of gene mutations that at present account for retinitis pigmentosa in approximately 50% of families with dominant forms and from 5 to 10% of patients with recessive forms. It is reasonable to expect that mutations in additional genes will soon be identified to account for the disease in additional patients. Since these mutations have been identified in genes that affect rod photoreceptor function and provide a new basis for classification, our research on rod photoreceptor function will focus on patients with known mutations. The second development motivating this proposal is the successful modeling of the activation phase of transduction in rods by Lamb and Pugh. We have shown that the Lamb and Pugh model fits the leading edge of the humane rod ERG a-wave. Thus the a-wave provides a direct, quantitative measure of human rod photoreceptor activity. Since the Lamb and Pugh model is based on biochemical steps in the activation stage of transduction, it provides a powerful framework for relating defects in rod physiology to specific gene mutations in patients with RP. Proposed studies will evaluate amplification within the phototransduction cascade, deactivation mechanisms, photoreceptor renewal mechanisms, and regional variations in photoreceptor function. Many patients with dominant forms of RP, and most patients with X-linked forms of RP, have lower than normal levels of an omega-3 fatty acid (FA), docosahexaenoic acid (DHA), in red blood cell (RBC) lipids. It is unlikely that omega-3 FA abnormalities cause retinitis pigmentosa but, given the important role of DHA in photoreceptor membrane function, DHA deficiency may influence the rate of progression. We have been following a large group of patients at yearly intervals with sensitive ERG and psychophysical measures of rod and cone function. We will obtain blood samples for both DNA and lipid analyses and relate both to phenotype and rate of progression. Morphological studies in donor eyes have shown ganglion cell loss in RP. Recently, a new imaging technology based on the scanning laser ophthalmoscope has been developed to measure the thickness of the nerve fiber layer. This methodology, known as retinal laser ellipsometry, utilizes the fact that the nerve fiber layer is a birefringent structure that polarizes light passing through it and the thickness of the layer is indexed by the amount of reflected polarized light. Measures of nerve fiber layer thickness in patients with RP will be compared with visual field loss, duration of loss, phenotype and genotype. These studies will provide the first in vivo, quantitative measures of the degree of transneuronal ganglion cell degeneration in patients with RP.
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