Role of homocysteine in retinal disease

Summary

Principal Investigator: Sylvia B Smith
Abstract: DESCRIPTION (provided by applicant): The goal of this project is to determine how elevated levels of homocysteine (Hcy) (hyperhomocysteinemia, HHcy)) contribute to retinal neurovascular disease. HHcy is implicated in retinal vascular occlusive disease, optic neuropathies (e.g. pseudoexfoliation glaucoma), macular degeneration, and diabetic retinopathy. Mild HHcy occurs in ~5%-12% of the population;hence understanding how HHcy contributes to retinal disease is critically important. Hcy is a key intermediate in methionine metabolism. HHcy is due to genetic defects involving cystathionine synthase (CBS), methylenetetrahydrofolate reductase (MTHFR) or methionine synthase as well as vitamin deficiencies (folate/B12/B6). During the previous funding period we analyzed retinas of mice with endogenous HHcy due to deficiency/lack of CBS and observed profound loss of visual function, marked disruption of retinal neuronal layers and florid vasculopathy in cbs-/- mice, and a milder phenotype with vascular alterations, progressive ganglion cell loss, dysregulation of axonal mitochondrial dynamics and delayed visual evoked potentials in cbs+/- mice. These data suggest that HHcy compromises retinal structure/function, the severity of which correlates with Hcy levels;and that HHcy alters retinal vasculature initially, subsequently triggering retinal neuron death. The phenotype may be due to increased ER stress, oxidative stress, and/or excitotoxicity;however since CBS irreversibly converts Hcy to cystathionine via the "transsulfuration pathway" leading to formation of cysteine, which is then converted to glutathione (GSH), hydrogen sulfide (H2S), and/or taurine, the observed disrupted retinal structure/function may be due to decreased levels of these downstream factors critical for retinal health. To investigate this, we will analyze retinas of mice lacking/deficient in MTHFR. mthfr mice have a defect in the "remethylation pathway" with concomitant HHcy;however their transsulfuration pathway is intact. Using these models we can dissect the role of HHcy in retina. Upon completion of the studies we will be poised to investigate whether folate/B12/B6 supplementation reverses/retards retinal neurovasculopathy associated with HHcy due to mutations in CBS or mthfr. There are three aims proposed for this study: Aim 1: Test the hypotheses that (A) HHcy compromises retinal structure/function regardless whether due to a defect in the transsulfuration or remethylation pathway;and (B) severe HHcy alters retinal vasculature initially, which subsequently triggers widespread death of retinal neurons (vasculopathy precedes neuropathy) while mild HHcy induces modest vascular changes disrupting only the inner retina;Aim 2: Test the hypothesis that HHcy due to CBS deficiency induces retinal neurovascular disease not only by inducing oxidative stress, excitotoxicity, and/or ER stress, but also by altering levels of GSH, H2S and taurine, whereas HHcy due to MTHFR deficiency induces retinal neurovascular disease through the oxidative stress, excitotoxicity, and/or ER stress pathways;Aim 3: Test the hypothesis that folate/B12/B6 supplementation will retard/reverse HHcy-induced retinal neurovasculopathy.
Funding Period: 1999-12-01 - 2017-02-28
more information: NIH RePORT

Top Publications

  1. pmc Expression of the cystine-glutamate exchanger (xc-) in retinal ganglion cells and regulation by nitric oxide and oxidative stress
    Y Dun
    Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd, CB 2820, Augusta, GA 30912 2000, USA
    Cell Tissue Res 324:189-202. 2006
  2. pmc Sensitivity of staurosporine-induced differentiated RGC-5 cells to homocysteine
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    Curr Eye Res 35:80-90. 2010
  3. pmc Molecular and biochemical characterization of folate transport proteins in retinal Müller cells
    B Renee Bozard
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    Invest Ophthalmol Vis Sci 51:3226-35. 2010
  4. pmc Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons
    Yonju Ha
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912 2000, USA
    Invest Ophthalmol Vis Sci 52:527-40. 2011
  5. pmc The role of N-methyl-D-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Georgia Health Sciences, University, Medical College of Georgia, Augusta, GA, USA
    Invest Ophthalmol Vis Sci 52:5515-24. 2011
  6. pmc Functional characterization of folate transport proteins in Staten's Seruminstitut rabbit corneal epithelial cell line
    J Jwala
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Curr Eye Res 36:404-16. 2011
  7. pmc Homocysteine-mediated modulation of mitochondrial dynamics in retinal ganglion cells
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia, USA
    Invest Ophthalmol Vis Sci 52:5551-8. 2011
  8. pmc Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate
    B Renee Bozard
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912 2000, USA
    Glia 60:333-42. 2012
  9. pmc Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia
    Minzhong Yu
    Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
    Exp Eye Res 96:124-31. 2012
  10. pmc The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities
    Jan Lewerenz
    Department of Neurology, University of Ulm, Ulm, Germany
    Antioxid Redox Signal 18:522-55. 2013

Research Grants

Detail Information

Publications26

  1. pmc Expression of the cystine-glutamate exchanger (xc-) in retinal ganglion cells and regulation by nitric oxide and oxidative stress
    Y Dun
    Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd, CB 2820, Augusta, GA 30912 2000, USA
    Cell Tissue Res 324:189-202. 2006
    ..Oxidative stress upregulates this transport system in RGC-5 cells, and the process is associated with an increase in xCT mRNA and protein but no change in 4F2hc mRNA or protein...
  2. pmc Sensitivity of staurosporine-induced differentiated RGC-5 cells to homocysteine
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    Curr Eye Res 35:80-90. 2010
    ..To understand mechanisms of homocysteine-induced cell death, we analyzed the sensitivity of the RGC-5 cell line, differentiated using staurosporine, to physiologically-relevant levels of the excitotoxic amino acid homocysteine...
  3. pmc Molecular and biochemical characterization of folate transport proteins in retinal Müller cells
    B Renee Bozard
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    Invest Ophthalmol Vis Sci 51:3226-35. 2010
    ..To analyze the mechanisms of folate uptake in retinal Müller cells...
  4. pmc Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons
    Yonju Ha
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912 2000, USA
    Invest Ophthalmol Vis Sci 52:527-40. 2011
    ..To investigate the mechanism of σ receptor 1 (σR1) neuroprotection in retinal neurons...
  5. pmc The role of N-methyl-D-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Georgia Health Sciences, University, Medical College of Georgia, Augusta, GA, USA
    Invest Ophthalmol Vis Sci 52:5515-24. 2011
    ..This study examined the role of the NMDA receptor in homocysteine-mediated ganglion cell death...
  6. pmc Functional characterization of folate transport proteins in Staten's Seruminstitut rabbit corneal epithelial cell line
    J Jwala
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO 64108 2718, USA
    Curr Eye Res 36:404-16. 2011
    ..The overall objective of this study was to investigate and characterize the expression of folate transport proteins in Staten's Seruminstitut rabbit corneal (SIRC) epithelial cell line...
  7. pmc Homocysteine-mediated modulation of mitochondrial dynamics in retinal ganglion cells
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia, USA
    Invest Ophthalmol Vis Sci 52:5551-8. 2011
    ..To evaluate the effect of excess homocysteine on the regulation of retinal ganglion cell mitochondrial dynamics...
  8. pmc Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate
    B Renee Bozard
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912 2000, USA
    Glia 60:333-42. 2012
    ..This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease...
  9. pmc Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia
    Minzhong Yu
    Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
    Exp Eye Res 96:124-31. 2012
    ..The work lays the foundation to explore the role of homocysteine in retinal diseases such as glaucoma and optic neuropathy...
  10. pmc The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities
    Jan Lewerenz
    Department of Neurology, University of Ulm, Ulm, Germany
    Antioxid Redox Signal 18:522-55. 2013
    ..Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x(c)(-) in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS...
  11. pmc Alterations of retinal vasculature in cystathionine-Beta-synthase mutant mice, a model of hyperhomocysteinemia
    Amany Tawfik
    Departments of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, USA
    Invest Ophthalmol Vis Sci 54:939-49. 2013
    ..Excess homocysteine is a risk factor for cardiovascular diseases; however, it is not known whether excess homocysteine alters retinal vasculature...
  12. pmc Evaluation of optic neuropathy in multiple sclerosis using low-contrast visual evoked potentials
    M J Thurtell
    Departments of Neurology, University Hospitals Case Medical Center, Cleveland, USA
    Neurology 73:1849-57. 2009
    ....
  13. pmc Absence of iron-regulatory protein Hfe results in hyperproliferation of retinal pigment epithelium: role of cystine/glutamate exchanger
    Jaya P Gnana-Prakasam
    Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
    Biochem J 424:243-52. 2009
    ..Wild-type mouse RPE cells and human RPE cell lines, when loaded with iron by exposure to ferric ammonium citrate, showed increased expression and activity of xCT, reproducing the biochemical phenotype observed with Hfe-/- RPE cells...
  14. ncbi Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta
    Sunao Sugita
    Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, 1 5 45 Yushima, Tokyo, Japan
    Exp Eye Res 83:1459-71. 2006
    ..We propose that this mechanism of suppression via TGFbeta ensures that soluble active TGFbeta is released into the ocular microenvironment in order to create the immune privilege of the posterior segment of the eye...
  15. pmc Functional and molecular analysis of D-serine transport in retinal Müller cells
    Y Dun
    Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd, CB 2820, Augusta, GA 30912 2000, USA
    Exp Eye Res 84:191-9. 2007
    ....
  16. ncbi Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina
    Pamela M Martin
    Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Invest Ophthalmol Vis Sci 48:3356-63. 2007
    ..In the present study, the authors asked whether SMCT1 and SMCT2 are also expressed in retina and, if so, in which particular retinal cell types...
  17. ncbi Progesterone inhibits folic acid transport in human trophoblasts
    Elisa Keating
    Department of Biochemistry U38 FCT, Faculty of Medicine of Porto, University of Porto, Porto 4200 319, Portugal
    J Membr Biol 216:143-52. 2007
    ..These results suggest that progesterone inhibits RFC. In conclusion, our results show that progesterone, a sterol produced by the placenta, inhibits both FA uptake and efflux in BeWo cells and primary cultured human trophoblasts...
  18. pmc Prevention of excitotoxicity in primary retinal ganglion cells by (+)-pentazocine, a sigma receptor-1 specific ligand
    Ying Dun
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    Invest Ophthalmol Vis Sci 48:4785-94. 2007
    ..The purpose of the present study was to establish a physiologically relevant paradigm for testing the neuroprotective effect of (+)-PTZ in retinal ganglion cells (RGCs)...
  19. pmc Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types
    Nagavedi S Umapathy
    Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
    Invest Ophthalmol Vis Sci 48:5299-305. 2007
    ..In the present study, the expression of this novel transporter in the retina was determined, the mouse orthologue was cloned from retinal tissue, and its transport function was characterized...
  20. ncbi Serine racemase expression and D-serine content are developmentally regulated in neuronal ganglion cells of the retina
    Ying Dun
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    J Neurochem 104:970-8. 2008
    ..This represents the first report of neuronal expression of D-serine and serine racemase in the vertebrate retina and suggests an important contribution of neuronal D-serine during retinal development...
  21. pmc Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe
    Jaya P Gnana-Prakasam
    Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
    Biochem J 411:79-88. 2008
    ..We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function...
  22. pmc Expression and function of system N glutamine transporters (SN1/SN2 or SNAT3/SNAT5) in retinal ganglion cells
    Nagavedi S Umapathy
    Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Invest Ophthalmol Vis Sci 49:5151-60. 2008
    ..System N, consisting of SN1 (SNAT3) and SN2 (SNAT5), is the principal mediator of glutamine transport in retinal Müller cells. Mediators of glutamine transport in retinal ganglion cells were investigated...
  23. pmc Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-beta-synthase mutant mouse
    Preethi S Ganapathy
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912 2000, USA
    Invest Ophthalmol Vis Sci 50:4460-70. 2009
    ..To determine the effects of endogenous elevation of homocysteine on the retina using the cystathionine beta-synthase (cbs) mutant mouse...
  24. pmc Identification of a novel sodium-coupled oligopeptide transporter (SOPT2) in mouse and human retinal pigment epithelial cells
    Paresh P Chothe
    Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Invest Ophthalmol Vis Sci 51:413-20. 2010
    ....
  25. pmc Cystathionine beta synthase expression in mouse retina
    Shanu Markand
    Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912 2000, USA
    Curr Eye Res 38:597-604. 2013
    ..Given the plethora of studies using mouse retina as a model system, coupled with the importance of GSH in retina, we investigated CBS expression in mouse retina at the molecular and cell biological level...

Research Grants30

  1. Coupled level set framework for retinal segmentation and atlasing in SD-OCT
    Jerry L Prince; Fiscal Year: 2013
    ..The developed software will be developed within the open-source Java Image Science Toolkit (JIST) framework and released as open source software. ..
  2. Indiana University Center for Pediatric Pharmacology
    Jamie L Renbarger; Fiscal Year: 2013
    ..The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. ..
  3. Vitamin B6 Effects on One-Carbon Metabolism
    Jesse F Gregory; Fiscal Year: 2013
    ..These studies will expand our understanding of the functional impact of vitamin B6 inadequacy in OC users and will provide a metabolically validated supplementation strategy to alleviate low B6 status and promote health in OC users. ..
  4. Parenteral Methionine Requirements in Septic Children
    Leticia Castillo; Fiscal Year: 2013
    ..In summary, our overall objective is to generate data to support changes on nutritional policy on parenteral sulfur amino acid intakes, and in the future test the impact of our established requirements on clinically relevant outcomes. ..
  5. Enzymology of H2S Biogenesis
    RUMA V BANERJEE; Fiscal Year: 2013
    ....
  6. Mechanisms of Diabetic Retinopathy: Oxidative Stress and Inflammation
    Ruth B Caldwell; Fiscal Year: 2013
    ..in preventing dysregulated ROS, inflammatory reactions and dysfunction of BM-derived and retinal cells with those of novel agents designed to release NO as well as scavenge superoxide and hydroxyl radicals and decompose peroxynitrite ..
  7. Jules Stein Eye Institute Core Grant for Vision Research
    Wayne L Hubbell; Fiscal Year: 2013
    ..Support in the form of the Core grant is requested to maintain these Modules through instrument service contracts, and to provide necessary personnel support to assist and train users and provide routine maintenance. ..
  8. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  9. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  10. SYNAPTIC TRANSMISSION AND ITS MODULATION IN THE RETINA
    Peter D Lukasiewicz; Fiscal Year: 2013
    ..In aim 2, we determine the circuits and synaptic mechanisms that produce the adaptational changes in center-surround spatial processing caused by different ambient light levels. ..
  11. Role of mechanosensation in retinal function and dysfunction
    David Krizaj; Fiscal Year: 2013
    ..This may help to refine our understanding of mechanical injury in vision disorders such as glaucoma, diabetic retinopathy and ischemia and contribute to developing effective neuroprotective treatments. ..
  12. 5Lipoxygenase-mediated vasculopathy in HHcy
    Domenico Pratico; Fiscal Year: 2013
    ..In the third one, we will establish the role of HHcy, and 5-LO upregulation in the development of the pathological vascular phenotype of the Tg-hCBS Cbs-/- mice. ..
  13. Mechanism of SIRT1 activator mediated neuroprotection of retinal ganglion cells
    Kenneth S Shindler; Fiscal Year: 2013
    ..Generation of ROS that induce oxidative stress will be examined, and mitochondrial numbers and function will be assessed to determine whether RGC survival is promoted by reducing oxidative stress. ..
  14. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  15. Methods for Pathway Modeling with Application to Folate
    Duncan C Thomas; Fiscal Year: 2013
    ....
  16. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  17. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..