The overall long-term goal is to understand cellular mechanisms in photoreceptor and RPE cells, especially those mechanisms related to the turnover of phototransductive proteins.
The specific aims of the present proposal focus on understanding the retinal function of the Usher 1B protein, myosin VIIa, which participates in this turnover process. Usher syndrome 1 (USH1) is a devastating disorder in which children are born with profound deafness and vestibular dysfunction. Later, they develop retinal degeneration. USH1 can be caused by mutations in any one of seven genes, although the most common genetic defect is in myosin VIIa (MYO7A). Our past studies have localized myosin VIIa in the retina, identified retinal phenotypes in myosin VIIa-mutant mice, and demonstrated actin-based motility of native myosin VIIa. The in vivo bias of these studies has permitted the development of physiologically relevant hypotheses about the retinal function of myosin VIIa. The proposed research tests these hypotheses at a more molecular and cellular level. We will investigate the role of myosin VIIa in the clearance of phagosomes from the apical to the basal region of the retinal pigmented epithelium (RPE). We will identify binding proteins in the RPE and photoreceptor cells, focusing on those that might link myosin VIIa to indicated roles in the localization of phagosomes, melanosomes, and opsin. We will test whether rhodopsin regeneration is inhibited in myosin VIIa-null RPE, as suggested by the finding that susceptibility to light damage is decreased in the absence of myosin VIIa. Lastly, we will investigate other USH1 proteins in the retina, and whether they interact with myosin VIIa. These studies will provide new information on the retinal function of myosin VIIa, and help elucidate the basis of retinal disease in USH1B.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007042-20
Application #
6998431
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Mariani, Andrew P
Project Start
1986-09-30
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
20
Fiscal Year
2006
Total Cost
$371,070
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Orme, Mariam H; Liccardi, Gianmaria; Moderau, Nina et al. (2016) The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles. Nat Commun 7:10972
Hazim, Roni; Jiang, Mei; Esteve-Rudd, Julian et al. (2016) Live-Cell Imaging of Phagosome Motility in Primary Mouse RPE Cells. Adv Exp Med Biol 854:751-5
Frost, Laura S; Lopes, Vanda S; Bragin, Alvina et al. (2015) The Contribution of Melanoregulin to Microtubule-Associated Protein 1 Light Chain 3 (LC3) Associated Phagocytosis in Retinal Pigment Epithelium. Mol Neurobiol 52:1135-1151
Volland, Stefanie; Esteve-Rudd, Julian; Hoo, Juyea et al. (2015) A comparison of some organizational characteristics of the mouse central retina and the human macula. PLoS One 10:e0125631
Strong, Randy; Miller, Richard A; Astle, Clinton M et al. (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68:6-16
Ashraf, Shazia; Gee, Heon Yung; Woerner, Stephanie et al. (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179-89
Frost, Laura S; Lopes, Vanda S; Stefano, Frank P et al. (2013) Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium. Vis Neurosci 30:55-64
Lopes, V S; Boye, S E; Louie, C M et al. (2013) Retinal gene therapy with a large MYO7A cDNA using adeno-associated virus. Gene Ther 20:824-33
Da Cruz, Sandrine; Parone, Philippe A; Lopes, Vanda S et al. (2012) Elevated PGC-1? activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab 15:778-86
Harkewicz, Richard; Du, Hongjun; Tong, Zongzhong et al. (2012) Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem 287:11469-80

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