The photoreceptor outer segment is an elaborate primary cilium. The delivery of opsin into and along the cilium is critical for photoreceptor cell function and viability. The overall goal of this study is to understand the cellular mechanisms involved in these delivery processes. A combination of cell biological methods, including imaging of protein movements in the cilium of live mouse photoreceptor cells, will be used. Studies will address questions about opsin entry into and transport along the cilium, and the membrane diffusion barrier of the photoreceptor cilium. The proposed research incorporates technical innovation, including the measurements of real-time movements of opsin along the cilium, using a ciliated epithelial cell line and mouse rod photoreceptor cells. It will test novel concepts of opsin trafficking and the organization of the photoreceptor cilium.

Public Health Relevance

The proposed research will provide a fundamental mechanistic understanding of cellular processes in the photoreceptor cilium. It will provide insight into the pathogenesis of a wide range of diseases, known as ciliopathies, which include retinal degeneration. There will also be tangible benefits to preclinical studies for retinal degeneration therapies, in that mutant phenotypes, which can be used to assess therapeutic efficacy, are likely to be identified by the research.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01EY013408-08
Application #
8656112
Study Section
(BVS)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Crouse, Jacquelin A; Lopes, Vanda S; Sanagustin, Jovenal T et al. (2014) Distinct functions for IFT140 and IFT20 in opsin transport. Cytoskeleton (Hoboken) 71:302-10
Zariwala, Maimoona A; Gee, Heon Yung; Kurkowiak, Malgorzata et al. (2013) ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am J Hum Genet 93:336-45
Trivedi, Deepti; Williams, David S (2010) Ciliary transport of opsin. Adv Exp Med Biol 664:185-91
Louie, Carrie M; Caridi, Gianluca; Lopes, Vanda S et al. (2010) AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet 42:175-80
Schwander, Martin; Lopes, Vanda; Sczaniecka, Anna et al. (2009) A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells. J Neurosci 29:15810-8
Avasthi, Prachee; Watt, Carl B; Williams, David S et al. (2009) Trafficking of membrane proteins to cone but not rod outer segments is dependent on heterotrimeric kinesin-II. J Neurosci 29:14287-98
Jimeno, David; Lillo, Concepcion; Roberts, Elizabeth A et al. (2006) Kinesin-2 and photoreceptor cell death: requirement of motor subunits. Exp Eye Res 82:351-3
Sayer, John A; Otto, Edgar A; O'Toole, John F et al. (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38:674-81
Jimeno, David; Feiner, Leonard; Lillo, Concepcion et al. (2006) Analysis of kinesin-2 function in photoreceptor cells using synchronous Cre-loxP knockout of Kif3a with RHO-Cre. Invest Ophthalmol Vis Sci 47:5039-46
Chang, Bo; Khanna, Hemant; Hawes, Norman et al. (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15:1847-57

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