The goal of the proposed research is to more fully exploit the fruitfly, Drosophila melanogaster, as an animal model for retinal degeneration. The Drosophila visual system has proven to be a very powerful genetic model to identify genes required for phototransduction and for photoreceptor cell survival. Over the last funding period, we set out to increase the pace of gene discovery by combining a comprehensive microarray analysis for """"""""eye-enriched"""""""" genes with new large-scale screens for mutations that cause defects in visual transduction. It now appears that most of the genes essential for phototransduction are in hand. Mutations in virtually all of these result in retinal degeneration. The goal of the research proposed here focuses on this medically important phenomenon. We propose to develop additional fly models for retinal degeneration, with a new emphasis on those genes that function in processes other than phototransduction. This is an important transition in our research, since the genes that cause retinal dystrophies in humans are not restricted to those that contribute to phototransduction, but function in many additional processes, such as protein transport, cytoskeletal function, lysosomal function and sphingolipid metabolism. Moreover, many of the retinal degeneration diseases are syndromic and cause clinical manifestations outside the visual system. Multiple retinal diseases also result from defects in the production and regeneration of the chromophore in the retinal pigment epithelium. Currently, flies have not been exploited as an animal model for diseases originating in the retinal pigment epithelium or for syndromic diseases. The four specific aims of the current research are to fill these voids by developing new retinal degeneration models in Drosophila. Moreover, based on our preliminary results, we propose that studying seemingly diverse models for retinal degeneration in parallel will promote the discovery of common underlying mechanisms, raising the possibility of identifying common therapies. To accomplish our goals, we propose to employ a multidisciplinary approach using a combination of genetic, cell biological, germline transformation, electrophysiological, biochemical and microarray techniques, which we have employed over the past 19 years to dissect the molecular mechanisms of phototransduction.

Public Health Relevance

The proposed research is to uses the fruitfly as an animal model to identify and characterize new genes and proteins associated with retinal degeneration. The long-term goal of the proposed research is to identify new therapies to reduce the severities of human retinal degenerations.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of California Santa Barbara
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Santa Barbara
United States
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Liu, Jiangqu; Sokabe, Takaaki; Montell, Craig (2018) A Temperature Gradient Assay to Determine Thermal Preferences of Drosophila Larvae. J Vis Exp :
Leung, Nicole Y; Montell, Craig (2017) Unconventional Roles of Opsins. Annu Rev Cell Dev Biol 33:241-264
Ni, Jinfei D; Baik, Lisa S; Holmes, Todd C et al. (2017) A rhodopsin in the brain functions in circadian photoentrainment in Drosophila. Nature 545:340-344
Sokabe, Takaaki; Chen, Hsiang-Chin; Luo, Junjie et al. (2016) A Switch in Thermal Preference in Drosophila Larvae Depends on Multiple Rhodopsins. Cell Rep 17:336-344
Hofmann, Lukas; Tsybovsky, Yaroslav; Alexander, Nathan S et al. (2016) Structural Insights into the Drosophila melanogaster Retinol Dehydrogenase, a Member of the Short-Chain Dehydrogenase/Reductase Family. Biochemistry 55:6545-6557
Walker, Marquis T; Montell, Craig (2016) Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation. Hum Mol Genet 25:2752-2761
Walker, Marquis T; Rupp, Alan; Elsaesser, Rebecca et al. (2015) RdgB2 is required for dim-light input into intrinsically photosensitive retinal ganglion cells. Mol Biol Cell 26:3671-8
Chen, Zijing; Chen, Hsiang-Chin; Montell, Craig (2015) TRP and Rhodopsin Transport Depends on Dual XPORT ER Chaperones Encoded by an Operon. Cell Rep 13:573-584
Liu, Chao; Montell, Craig (2015) Forcing open TRP channels: Mechanical gating as a unifying activation mechanism. Biochem Biophys Res Commun 460:22-5
Akitake, Bradley; Ren, Qiuting; Boiko, Nina et al. (2015) Coordination and fine motor control depend on Drosophila TRP?. Nat Commun 6:7288

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