Leber congenital amaurosis (LCA), the most severe form of inherited retinal dystrophy, causes blindness or impaired vision at birth. In agreement with the severity of LCA caused by mutations in Aryl hydrocarbon receptor interacting protein like-1 (Aipl1), a mouse model for this disease shows rapid degeneration of rod and cone photoreceptor cells. Although photoreceptor cells form normally in Aipl1-/- mice, neither rods nor cones are functional. Rapid rod degeneration in Aipl1-/- mice is caused by loss of functional rod phosphodiesterase (PDE), an enzyme essential for phototransduction and photoreceptor viability. However, the relationship between AIPL1 and PDE stability is not yet known. Rapid degeneration of cones in Aipl1-/- mice suggests that AIPL1 is also important for cone function and viability. But, the function of AIPL1 in cone photoreceptors is not yet known. We propose to use a combination of ex vivo biochemical analyses together with tissue culture expression analysis and transgenic rescue to reveal the essential role of AIPL1 in PDE stability and photoreceptor viability.
The specific aims of this study are to: 1. Determine the role of AIPL1 in post-translational regulation of PDE in rods. 2. Investigate the requirement of AIPL1 for the function and survival of cone photoreceptors. The long-term goals of this study are to elucidate the role of AIPL1 in retina, understand the mechanisms by which defects in AIPL1 contribute to rapid retinal degeneration, and to lay the groundwork for the development of therapeutic approaches to the disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017035-04
Application #
7784419
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2007-04-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$326,329
Indirect Cost
Name
West Virginia University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Christiansen, Jeffrey R; Pendse, Nachiket D; Kolandaivelu, Saravanan et al. (2016) Deficiency of Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Leads to Progressive Loss of Photoreceptor Function. J Neurosci 36:5107-14
Wright, Zachary C; Singh, Ratnesh K; Alpino, Ryan et al. (2016) ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment. Hum Mol Genet 25:2031-2044
Murphy, Daniel; Kolandaivelu, Saravanan; Ramamurthy, Visvanathan et al. (2016) Analysis of Alternative Pre-RNA Splicing in the Mouse Retina Using a Fluorescent Reporter. Methods Mol Biol 1421:269-86
Ku, Cristy A; Chiodo, Vince A; Boye, Sanford L et al. (2015) Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model. Hum Mol Genet 24:670-84
Murphy, Daniel; Singh, Ratnesh; Kolandaivelu, Saravanan et al. (2015) Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa. Mol Cell Biol 35:1860-70
Kolandaivelu, Saravanan; Ramamurthy, Visvanathan (2014) AIPL1 protein and its indispensable role in cone photoreceptor function and survival. Adv Exp Med Biol 801:43-8
Singh, Ratnesh Kumar; Kolandaivelu, Saravanan; Ramamurthy, Visvanathan (2014) Early alteration of retinal neurons in Aipl1-/- animals. Invest Ophthalmol Vis Sci 55:3081-92
Kolandaivelu, Saravanan; Singh, Ratnesh K; Ramamurthy, Visvanathan (2014) AIPL1, A protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells. Hum Mol Genet 23:1002-12
Deng, Wen-Tao; Sakurai, Keisuke; Kolandaivelu, Saravanan et al. (2013) Cone phosphodiesterase-6?' restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6?-deficient rd10 mouse. J Neurosci 33:11745-53
Majumder, Anurima; Pahlberg, Johan; Boyd, Kimberly K et al. (2013) Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells. Proc Natl Acad Sci U S A 110:12468-73

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