RETINAL DEHYDROGENASES

Summary

Principal Investigator: JOSEPH NAPOLI
Abstract: DESCRIPTION (provided by applicant): The long-term goals of my research program include defining the biochemical, molecular and endocrine aspects of RA (retinoic acid) biosynthesis. This project will focus on the second step in the pathway of RA biogenesis from retinol (vitamin A), catalyzed by RALDH1-4 (retinal dehydrogenase types 1-4), and will test the umbrella hypothesis that each RALDH makes a unique and essential contribution to RA biogenesis. Specific Aims 1 would determine the contribution of RALDH 1, 2 and 3 to RA biosynthesis in the brain, focusing on the hippocampus. This aim would test the hypotheses that: hippocampus neurons biosynthesize RA from retinol;BDNF enhances neuron conversion of retinol into RA;BDNF functions by increasing RALDH3 mRNA and protein;and exogenous retinoids alter RA biosynthesis in the brain. This aim will include quantifying RA concentrations in specific brain areas by LC/MS/MS (lower limit of detection of 10 fmol) during aging and treatment with exogenous retinoids. Specific Aims 2-4 will: 2) generate and evaluate RALDH4-null mice;3) identify the RALDH 1 gene regulatory regions that mediate tissue-specific responses to retinoids in vivo;4) generate and evaluate conditional RALDH2 knockouts. Each of these aims represents a logical progression in evaluating the specific contribution of an RALDH or RALDHs to RA biosynthesis. Each aim will rely on integrating molecular genetics approaches (transgenics and knockouts) with analytical techniques (hplc, LC/MS) and applying both to metabolic studies in vitro and in the whole animal. The fundamental insight and reagents generated will be useful to identify diseases and age-related degeneration that may be caused or exacerbated by impaired RA biosynthesis.
Funding Period: 1995-07-10 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Ethanol elevates physiological all-trans-retinoic acid levels in select loci through altering retinoid metabolism in multiple loci: a potential mechanism of ethanol toxicity
    MAUREEN A KANE
    119 Morgan Hall, MC 3104, University of California, Berkeley, Berkeley, CA 94720 3104, USA
    FASEB J 24:823-32. 2010
  2. pmc Binding affinities of CRBPI and CRBPII for 9-cis-retinoids
    MAUREEN A KANE
    Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720 3104, USA
    Biochim Biophys Acta 1810:514-8. 2011
  3. ncbi All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha
    Na Chen
    Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA
    FASEB J 22:236-45. 2008
  4. pmc Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry
    MAUREEN A KANE
    Department of Nutritional Science and Toxicology, 119 Morgan Hall, MC 3104, University of California, Berkeley, Berkeley, California 94720 3104, USA
    Anal Chem 80:1702-8. 2008
  5. pmc HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues
    MAUREEN A KANE
    Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA
    Anal Biochem 378:71-9. 2008
  6. pmc The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation
    Na Chen
    Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA
    J Biol Chem 283:20841-7. 2008
  7. pmc Rdh12 activity and effects on retinoid processing in the murine retina
    Jared D Chrispell
    Departments of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA
    J Biol Chem 284:21468-77. 2009

Detail Information

Publications8

  1. pmc Ethanol elevates physiological all-trans-retinoic acid levels in select loci through altering retinoid metabolism in multiple loci: a potential mechanism of ethanol toxicity
    MAUREEN A KANE
    119 Morgan Hall, MC 3104, University of California, Berkeley, Berkeley, CA 94720 3104, USA
    FASEB J 24:823-32. 2010
    ..Kane, M. A., Folias, A. E., Wang, C., Napoli, J. L. Ethanol elevates physiological all-trans-retinoic acid levels in select loci through altering retinoid metabolism in multiple loci: a potential mechanism of ethanol toxicity...
  2. pmc Binding affinities of CRBPI and CRBPII for 9-cis-retinoids
    MAUREEN A KANE
    Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720 3104, USA
    Biochim Biophys Acta 1810:514-8. 2011
    ..This study extended current knowledge by establishing binding affinities for CRBPI and CRBPII with 9-cis-retinoids...
  3. ncbi All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha
    Na Chen
    Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA
    FASEB J 22:236-45. 2008
    ..These data provide mechanistic insight into atRA function in the hippocampus and identify a unique membrane-associated RARalpha that mediates rapid induction of neuronal translation by atRA...
  4. pmc Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry
    MAUREEN A KANE
    Department of Nutritional Science and Toxicology, 119 Morgan Hall, MC 3104, University of California, Berkeley, Berkeley, California 94720 3104, USA
    Anal Chem 80:1702-8. 2008
    ..g., in neurogenesis, morphogenesis, and the contribution of altered RA homeostasis to diseases, such as Alzheimer's disease, type 2 diabetes, obesity, and cancer...
  5. pmc HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues
    MAUREEN A KANE
    Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA
    Anal Biochem 378:71-9. 2008
    ..The assays described here provide for sensitive and rigorous quantification of endogenous RE, ROL, and RAL to elucidate retinoid homeostasis in disease states such as Alzheimer's disease, type 2 diabetes, obesity, and cancer...
  6. pmc The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation
    Na Chen
    Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA
    J Biol Chem 283:20841-7. 2008
    ..These data afford a mechanism for rapid stimulation of dendritic growth by all-trans-retinoic acid and reveal that the ligand-dependent transcription factor RARalpha also regulates translation...
  7. pmc Rdh12 activity and effects on retinoid processing in the murine retina
    Jared D Chrispell
    Departments of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA
    J Biol Chem 284:21468-77. 2009
    ..Our findings suggest that a critical function of RDH12 is the reduction of all-trans-retinal that exceeds the reductive capacity of the photoreceptor outer segments...