The long term goal of this research is to understand cellular mechanisms in photoreceptor cells, especially those involved in turnover of the phototransductive membrane. The proposed plan is to focus on understanding the role of myosin VIIa in the retina. Myosin VIIa is the product of the gene defective in Usher syndrome type 1B, which accounts for about 50 percent of all Usher syndrome cases. Usher syndrome is the most common inherited blindness-deafness disorder, and accounts for about 17 percent of all cases of retinitis pigmentosa. Preliminary studies suggest a role for myosin VIIa in the turnover of phototransductive membrane. The proposed studies will use shaker-1 mice, which are mutant for myosin VIIa, to study the in vivo retinal function of myosin VIIa. In addition, purified myosin VIIa will be used to investigate protein structure and function in vitro. In studies leading up to those proposed, we localized myosin VIIa in the connecting cilia of the photoreceptor cells and, as others had found, in the apical processes of the retinal pigment epithelium (RPE). Here, the photoreceptor cells and the RPE cells will be examined in different alleles of shaker-1 mice to determine the cellular phenotypes resulting from mutant myosin VIIa. To complement the studies on shaker-1 mice, the quaternary structure and biochemical properties of myosin VIIa will be investigated. These studies will include tests of the capabilities of myosin VIIa. Thus they will test the fit of hypotheses proposed for the retinal function of myosin VIIa from the studies on shaker-1 mice. In this respect, questions to be addressed include: does the protein exhibit myosin-like motor function, and how does it interact with suggested cargo? The proposed research is pertinent to: (1) The structure and function of an unconventional myosin; (2) The mystery of how opsin is delivered to the outer segment; and (3) Blindness in Usher syndrome 1B.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY007042-13
Application #
2690737
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1986-09-30
Project End
2003-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
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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