The long term goal of this research program is to understand how the phototransduction machinery is assembled, transported and maintained in outer segment (OS), as a prerequisite for preventing and/or repairing defects that arise when this process goes awry. We believe protein lipid modification plays a role in this process. We hypothesize that lipidation of proteins is a dynamic process and is essential in organizing and facilitating cross-talk between proteins in the phototransduction pathway at disc membranes. We will use phosophodiesterase-6 (PDE6) as a model protein to test this hypothesis. PDE6 is the crucial effectors enzyme needed for light signaling in rod and cone photoreceptor cells. Absence of PDE6 in ciliated OS in photoreceptor cells leads to vision loss accompanied by rapid degeneration. In humans, lack of PDE6 in OS leads to various blinding diseases such as retinitis pigmentosa, leber congenital amaurosis and achromatopsia. Despite our knowledge about the role of PDE6 as an effectors enzyme in phototransduction, how this crucial enzyme is assembled in inner segments, transported and then anchored in outer segment membranes is not known. The experiments proposed in this project are aimed at deciphering the mechanism behind the need for protein lipidation and further processing of PDE6 in survival and function of rods and cones. We plan to accomplish these goals by investigating the function, stability, assembly and transport of lipidated proteins including PDE6, in animal models that either expresses mutant forms of PDE6 or in models that lack specific enzymes that are responsible for these modifications. Finally, we will investigate the protein transport mechanisms in cone cells using these animal models. Our proposed studies are aligned with Retinal Diseases Program of the NEI to """"""""determine the pathophysiological mechanisms underlying mutations"""""""" that cause retinal degenerative diseases. Our proposed studies lay a framework by which we can understand the basis behind various blinding diseases and design novel therapies to treat them.

Public Health Relevance

Survival and function of rod and cone cells in retina depends on efficient synthesis and transport of protein machinery from inner segments to ciliated outer segment. Defects in this process lead to debilitating blinding diseases in humans. This proposal will elucidate the role of protein lipid modification in trafficking and function of crucial proteis in rods and cones and lay a framework by which we can understand the basis behind blinding diseases and design novel treatments for these diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Shen, Grace L
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West Virginia University
Schools of Medicine
United States
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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
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
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
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
Kolandaivelu, Saravanan; Ramamurthy, Visvanathan (2014) AIPL1 protein and its indispensable role in cone photoreceptor function and survival. Adv Exp Med Biol 801:43-8
Deng, Wen-Tao; Sakurai, Keisuke; Kolandaivelu, Saravanan et al. (2013) Cone phosphodiesterase-6α' restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6β-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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