This application involves three general areas of ocular research: 1) retinol transport, 2) neurotransmitters and electrical synapses, and 3) photoreceptor shedding and recognition. With the aid of cytochemical markers we will define the ultrastructural distribution of serum retinol binding protein receptors on the surface of the in situ and cultured retinal pigment epithelium. In addition, these membrane receptors will be biochemically isolated and characterized. We will study the intracellular uptake of retinol medited by these receptors in in situ and cultured pigment epithelium. Having delivered retinol intracellularly via the membrane receptor, we will disrupt the cells and isolate and characterize the protein(s) that protect and transport retinol within the cytosol. Finally, we will study the secretion of retinol by pigment epithelial cells and attempt to isolate the transport protein(s) involved in this process. The sites of snythesis and transport of an enzyme responsible for the synthesis of Gamma-amino butyric acid will be studied by electron microscopic immunocytochemistry. Ultractructural cytochemical methods will also be employed to localize putative acetylcholine receptors on various retinal subtypes. The electrical synapse (gap junction) distribution will also be studied in the retina by immunocytochemical means, and comparisons will be made between these junctions and those of the lens which are thought to be immunologically unique. Experiments are described which probe the mechanism for outer segment disc-shedding and recognition by the pigment epithelium during outer segment renewal. We will attempt to suppress shedding by interfering with melatonin synthesis and block recognition by masking molecules assumed to effect the recognition process. Retinol transport is crucial to vision for its role in photoreception and tissue maintenance. The development of specific membrane receptor markers is essential for measuring cell homogeneity in tissue cultures and for cell identification in various proliferative diseases of the retina. knowledge of retinal neurotransmitters is fundamental to an understanding of retinal function and its susceptibility to pharmacological agents. An appreciation of mechanisms regarding disc-shedding and phagocytosis could help in the prevention or treatment of senile changes in the photoreceptor-pigment epithelial complex.

National Institute of Health (NIH)
National Eye Institute (NEI)
Method to Extend Research in Time (MERIT) Award (R37)
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University of California Los Angeles
Anatomy/Cell Biology
Schools of Medicine
Los Angeles
United States
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Mukherjee, Pranab K; Marcheselli, Victor L; Barreiro, Sebastian et al. (2007) Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling. Proc Natl Acad Sci U S A 104:13152-7
Ruiz, Alberto; Ghyselinck, Norbert B; Mata, Nathan et al. (2007) Somatic ablation of the Lrat gene in the mouse retinal pigment epithelium drastically reduces its retinoid storage. Invest Ophthalmol Vis Sci 48:5377-87
Bok, Dean (2007) Contributions of genetics to our understanding of inherited monogenic retinal diseases and age-related macular degeneration. Arch Ophthalmol 125:160-4
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Deora, Ami A; Philp, Nancy; Hu, Jane et al. (2005) Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia. Proc Natl Acad Sci U S A 102:16245-50
Rohrer, Baerbel; Blanco, Roman; Marc, Robert E et al. (2004) Functionally intact glutamate-mediated signaling in bipolar cells of the TRKB knockout mouse retina. Vis Neurosci 21:703-13
Deora, Ami A; Gravotta, Diego; Kreitzer, Geri et al. (2004) The basolateral targeting signal of CD147 (EMMPRIN) consists of a single leucine and is not recognized by retinal pigment epithelium. Mol Biol Cell 15:4148-65
Stamer, W Daniel; Bok, Dean; Hu, Jane et al. (2003) Aquaporin-1 channels in human retinal pigment epithelium: role in transepithelial water movement. Invest Ophthalmol Vis Sci 44:2803-8

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