Abstract

Photoreceptor outer segment membranes, the site of initial photon capture initiating phototransduction, undergo renewal with total replacement occurring at ten-day intervals throughout life. A challenge to cellular integrity concerns the post biosynthetic delivery of replacement proteins from the inner to the outer segment over the photoreceptor lifetime. Complex trafficking pathways require multiple components, e.g., UNC119 acyl-binding proteins, small GTPases such as ARL3, and GAP proteins like RP2. Mutations in UNC119 and RP2 are associated with cone-rod dystrophy and X-linked retinitis pigmentosa, respectively. This application will: i) identify pathways for transducin transport in rods, particularly after light-induced translocation; and ii) generate knockout models for NPHP10 and devise gene replacement therapies for NPHP5 and NPHP10 LCA.

Public Health Relevance

We propose to generate a several knockout and/or knockdown mouse models to elucidate the function of key proteins involved in photoreceptor ciliopathies. The candidates for our research include UNC119/ARL3, NPHP5 and NPHP10. The ultimate goal is to understand mechanisms leading to human retina disease and design gene replacement therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008123-30
Application #
9452963
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
1989-12-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
30
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Ying, Guoxin; Boldt, Karsten; Ueffing, Marius et al. (2018) The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium. J Biol Chem 293:17546-17558
Hanke-Gogokhia, Christin; Wu, Zhijian; Sharif, Ali et al. (2017) The guanine nucleotide exchange factor Arf-like protein 13b is essential for assembly of the mouse photoreceptor transition zone and outer segment. J Biol Chem 292:21442-21456
Zhang, Yuxin; Deng, Wen-Tao; Du, Wei et al. (2017) Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy. Sci Rep 7:6690
Hanke-Gogokhia, Christin; Wu, Zhijian; Gerstner, Cecilia D et al. (2016) Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors. J Biol Chem 291:7142-55
Rao, Kollu N; Zhang, Wei; Li, Linjing et al. (2016) Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR. Hum Mol Genet 25:2005-2012
Rainy, Nir; Etzion, Talya; Alon, Shahar et al. (2016) Knockdown of unc119c results in visual impairment and early-onset retinal dystrophy in zebrafish. Biochem Biophys Res Commun 473:1211-1217
Ma, Hongwei; Butler, Michael R; Thapa, Arjun et al. (2015) cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice. J Biol Chem 290:20880-92
Jiang, Li; Wei, Yuxiao; Ronquillo, Cecinio C et al. (2015) Heterotrimeric kinesin-2 (KIF3) mediates transition zone and axoneme formation of mouse photoreceptors. J Biol Chem 290:12765-78
Tracy, Christopher M; Kolesnikov, Alexander V; Blake, Devon R et al. (2015) Retinal cone photoreceptors require phosducin-like protein 1 for G protein complex assembly and signaling. PLoS One 10:e0117129
Zhang, Houbin; Hanke-Gogokhia, Christin; Jiang, Li et al. (2015) Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. FASEB J 29:932-42

Showing the most recent 10 out of 126 publications