Biography
Neurochemical and Anatomical Pathways in the Vertebrate Retina that Mediate Vision Dr. Brecha’s major research interest is concerned with understanding the functional organization of the mammalian retina by elucidating its morphology and neurochemistry. Specific investigations are focused on defining the microcircuitry of the inner retina, evaluating the neurochemical organization and regulation of both its fast (amino acid) and slow (peptide) transmitter systems, and the function of bipolar, amacrine and ganglion cell populations, which are major retinal cell types that play critical roles in the processing of visual information. Recent investigations concerned with peptide-containing cell populations are defining the cellular expression patterns of tachykinin, somatostatin, neuropeptide Y and opiate receptors, and their functional role in modulating bipolar cell responsiveness. Morphological studies have shown that peptide receptor subtypes are selectively expressed by different populations of bipolar, amacrine and ganglion cells. These observations have provided important clues to the organization of the retinal microcircuits mediating different aspects of vision, as well as the sites of action of several previously identified retinal transmitter substances. A new research direction, developed over the past three years has been focused on determining the function of peptides in the retina. The rationale of these studies is to define the cellular actions of peptides found in the retina, which we hypothesize modulate cellular responsiveness, to influence ion channels and other intercellular messenger systems. Initial studies have focused on somatostatin; our findings demonstrate that this peptide inhibits both K+ and Ca2+ ion channels in the axonal terminals of bipolar cells and photoreceptors at low concentrations. Interestingly, these cells prominently express the somatostatin receptor subtype, sst2A suggesting this action is mediated through this receptor. These investigations provide further support for a role of somatostatin in the presynaptic modulation of transmitter release from retinal cells.
Biography
Retinal Cell and Molecular Biology Dr. Bok studies mechanisms whereby membrane receptors, retinoid binding proteins, and enzymes mediate the vectorial uptake, processing and release of retinoids by the retinal pigment epithelium (RPE). He also explores mechanisms whereby the RPE cells develop the polarity required for their diverse functions. A second major research effort involves the study of molecular mechanisms underlying degeneration of retinal photoreceptors. These degenerations come under the general disease categories of retinitis pigmentosa and macular degeneration in humans. Retinitis pigmentosa is a family of inherited blinding diseases. Macular degeneration can be either age related or inherited. The third field of study involves photoreceptor-RPE interactions in health and disease. This includes the development of transgenic mice in which the expression of a wild-type gene or its mutant counterpart can be induced by the administration of doxycycline. Major techniques used in Dr. Bok’s research include electron microscopy, laser confocal microscopy, light and electron microscopic autoradiography, cell culture, immunocytochemistry, in situ hybridization cytochemistry, molecular cloning/sequencing and analysis of transgenic animals. Contributions include the discovery of photoreceptor outer segment disc shedding, phagocytosis of these membranes by the RPE, the failure of this process in rat mutants (rdy), detection of membrane receptors for the uptake and release of retinoids by the RPE, transgenic rescue of inherited degeneration in mice carrying the rds mutation and the modeling of the equivalent human disease in mice through the introduction of point mutations in the mouse rds gene.
Publications
A selected list of publications:
Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. , Science, ; 315(5813): 820-5.
Radu RA, Yuan Q, Hu J, Peng JH, Lloyd M, Nusinowitz S, Bok D, Travis GH. Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation, Invest Ophthalmol Vis. Sci, 2008; 49(9): 3821-9.
Radu RA, Hu J, Peng J, Bok D, Mata NL, Travis GH. Retinal pigment epithelium-retinal G protein receptor-opsin mediates light-dependent translocation of all-trans-retinyl esters for synthesis of visual chromophore in retinal pigment epithelial cells, J Biol Chem, 2008; 283(28): 19730-8.
Brill E, Malanson KM, Radu RA, Boukharov NV, Wang Z, Chung HY, Lloyd MB, Bok D, Travis GH, Obin M, Lem J A novel form of transducin-dependent retinal degeneration: accelerated retinal degeneration in the absence of rod transducin, Invest Ophthalmol Vis. Sci, 2007; 48(12): 5445-53.
Bok D. Contributions of genetics to our understanding of inherited monogenic retinal diseases and age-related macular degeneration, Arch Oppthalmol, 2007; 125(2): 160-4.
Rhee KD, Ruiz A, Duncan JL, Hauswirth WW, Lavail MM, Bok D, Yang XJ. Molecular and cellular alterations induced by sustained expression of ciliary neurotrophic factor in a mouse model of retinitis pigmentosa, Invest Ophthalmol Vis. Sci, 2007; 48(3): 1389-400.
Mukherjee PK, Marcheselli VL, Barreiro S, Hu J, Bok D, Bazan NG. Neurotrophins enhance retinal pigment epithelial cell survival though neuroprotectin D1 signaling, Proc Natl Acad Sci U S A, 2007; 104(32): 13152-7.
Mukherjee PK, Marcheselli VL, Barreiro S, Hu J, Bok D, Bazan NG. Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling, Proc Natl Acad Sci U S A, 2007; 104(32): 13152-7.
Ruiz A, Ghyselinck NB, Mata N, Nusinowitz S, Lloyd M, Dennefeld C, Chambon P, Bok D. Somatic ablation of the Lrat gene in the mouse retinal pgiment epithelium drastically reduces its retinoid storage, Invest Ophthalmol Vis. Sci, 2007; 48(12): 5377-87.
Senanayake P, Calabro A, Hu JG, Bonilha VL, Darr A, Bok D, Hollyfield JG. Glucose utilization by the retinal pgment epithelium: evidence for rapid uptake and storage in glycogen, followed by glycogen utilization, Exp Eye Res, 2006; 83(2): 235-46.
Sheren-Manoff M, Shin SJ, Su D, Bok D, Rando RR, Gudas LJ. Reduced lecithin: retinol acyltransferase expression in human breast cancer, Int J Oncol, 2006; 29(5): 1193-9.
Mora RC, Bonilha VL, Shin BC, Hu J, Cohen-Gould L, Bok D, Rodriguez-Boulan E. Bipolar assembly of caveolae in retinal pigment epithelium, Am J Physiol Cell Physiol, 2005; 290(3): C832-43.
Bok D. Cellular mechanisms of retinal degenerations: RPE65, ABCA4, RDS, and bicarbonate transporter genes are examples, Retina, 2005; 25(8): S18-S20.
Bok D. Ciliary neurotrophic factor therapy for inherited retinal diseases: pros and cons, Retina, 2005; 25(8): S27-S28.
Bok D. Evidence for an inflammatory process in age-related macular degeneration gains new support, Proc Natl Acad Sci U S A, 2005; 102(20): 7053-4.
Deora AA, Philp N, Hu J, Bok D, Rodriguez-Boulan E. Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia, Proc Natl Acad Sci U S A, 2005; 102(45): 16245-50.
Radu RA, Han Y, Bui TV, Nusinowitz S, Bok D, Lichter J, Widder K, Travis GH, Mata NL. Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases, Invest Ophthalmol Vis Sci, 2005; 46(12): 4393-401.
Bok D. Retinal researchers have reasons to be optimistic, Retina, 2005; 25(8): S43.
Bok D. The role of RPE65 in inherited retinal diseases, Retina, 2005; 25(8): S61-S62.
Lopez IA, Acuna D, Galbraith G, Bok D, Ishiyama A, Liu W, Kurtz I. Time course of auditory impairment in mice lacking the electroneutral sodium bicarbonate cotransporter NBC3 (slc4a7), Brain Res Dev Brain Res, 2005; 160(1): 63-77.
Rohrer B, Blanco R, Marc RE, Lloyd MB, Bok D, Schneeweis DM, Reichardt LF. Functionally intact glutamate-mediated signaling in bipolar cells of the TRKB knockout mouse retina, Vis Neurosci, 2004; 21(5): 703-13.
Bok D. Gene therapy of retinal dystrophies: achievements, challenges and prospects, Novartis Found Symp, 2004; 255: 4-12.
Boorjian S, Tickoo SK, Mongan NP, Yu H, Bok D, Rando RR, Nanus DM, Scherr DS, Gudas LJ. Reduced lecithin: retinol acyltransferase expression correlates with increased pathologic tumor stage in bladder cancer, Clin Cancer Res, 2004; 10(10): 3429-3.
Deora AA, Gravotta D, Kreitzer G, Hu J, Bok D, Rodriguez-Boulum E. The basolateral targeting signal of CD147 (EMMPRIN) consists of a single leucine and is not recognized by retinal pigment epithelium, Mol Biol Cell, 2004; 15(9): 4148-65.
Zhan HC, Gudas LJ, Bok D, Rando R, Nanus DM, Tickoo SK. Differential expression of the enzyme that esterifies retinol, lecithin: retinol acyltransferase, in subtypes of human renal cancer and normal kidney, Clin Cancer Res, 2003; 9(13): 4897-905.
Bok D, Yasumura D, Matthes MT, Ruiz A, Duncan JL, Chappelow AV, Zolutukhin S, Hauswirth W and LaVail MM. Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation, Exp Eye Res, 2002; 74: 719-735.
Ruiz A, Kuehn MH, Andorf J, Stone E, Hageman GS and Bok D. Organization of the lecithin retinol acyltransferase gene and mutation screening in various human hereditary retinal degenerations, Invest. Ophthalmol. Vis. Sci, 2001; 42: 31-37.
Mondal, MS, Ruiz A, Bok D and Rando RR Lecithin retinol acyltransferse contains cysteine residues essential for catalysis, Biochemistry, 2000; 39: 5215-5220.
Ruiz, A Winston, A Lim, YH Gilbert, BA Rando, RR Bok, D Molecular and biochemical characterization of lecithin retinol acyltransferase The Journal of biological chemistry. , 1999; 274(6): 3834-41.
Kedzierski, W., Bok D. and Travis, G.H. Non cell-autonomous photoreceptor degeneration in rds mutant mice mosaic for expression of a rescue transgene, J. Neurosci, 1998; 18: 4076-4082.
Kingma, PB Bok, D Ong, DE Bovine epidermal fatty acid-binding protein: determination of ligand specificity and cellular localization in retina and testis Biochemistry. , 1998; 37(10): 3250-7.
Kedzierski, W Lloyd, M Birch, DG Bok, D Travis, GH Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors Investigative ophthalmology & visual science. , 1997; 38(2): 498-509.
Ruiz A., Bhat S.P. and Bok D. Expression and synthesis of the Na,K-ATPase b2 subunit in human retinal pigment epithelium, Gene, 1996; 176: 237-242.
Ruiz, A., Bhat, S.P. and Bok, D. Characterization and quantification of full-length and truncated Na,K-ATPase a1 and b1 transcripts expressed in human retinal pigment epithelium, Gene, 1995; 155: 179-184.
Ong, DE Davis, JT O’Day, WT Bok, D Synthesis and secretion of retinol-binding protein and transthyretin by cultured retinal pigment epithelium Biochemistry. , 1994; 33(7): 1835-42.
Bosch, E Horwitz, J Bok, D Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. , 1993; 41(2): 253-63.
