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DVM
Ralph Meyer

Ralph Meyer

Associate Professor
Program: Center for Integrated BioSystems
Animal, Dairy and Veterinary Sciences: DVM, Faculty , Research Faculty, Staff
Location:  CIB 211
Office Phone:  435-797-1774
Fax:  2766

Specialties: Environmental reproductive physiology, developmental biology

About Me

The main research interest in my laboratory has been focused on the impacts of the environment, nutrition and genetic predisposition on male fertility and heritable diseases with an epigenetic component. Several laboratories, including my own, have provided evidence that sperm carry an epigenetic program which contributes to the control of embryonic gene expression. This epigenetic program has been shown to be subject to change by gene-environment interactions, making males susceptible throughout their lifetime to adverse environmental factors with consequences that are passed on to the next generation.

Epigenetic information is layered on top of the genetic information provided by the DNA. Its known molecular basis consists for instance of DNA CpG methylation, chromatin modifications such as posttranslational modifications of histones, insulator proteins, and other proteins, as well as coding, and non-coding RNAs, and all of these have the potential to regulate gene activity. Changes to the sperm epigenetic program have been identified as likely causes of embryonic failure and epigenetic late-onset disease problems in his progeny, such as obesity, diabetes, cancer and behavioral changes.

Our long-term goal is to understand the relevant mechanisms of sperm epigenetic programming and its inheritance to the next generation which will help us to make adequate lifestyle choices and develop pharmacological intervention strategies to improve human and animal health.

I graduated from the University of Kaiserslautern in Germany as a Diplom Biologe (similar to M.S) with majors in Molecular Cell Biology and Botany in 1994. From 1995-1998 I completed my doctoral research on the role of poly(ADP-ribose) metabolism in DNA repair and carcinogenesis at the German Cancer Research Center (DKFZ) in Heidelberg, Germany. As a postdoctoral fellow, I worked on the development of viral vectors for gene therapy and human genetics at the University Hospital of the University of Tuebingen until 2001. From 2002-2005, I trained as an Assistant Research Scientist in the area of poly(ADP-ribose) metabolism as a pharmacological target for cancer therapy at the College of Pharmacy at Arizona Cancer Center at the University of Arizona under the guidance of Myron K. Jacobson. I was also involved in R & D as a scientist at Niadyne Pharma Inc. at that time. In 2005, I accepted a position as Assistant Professor at the University of Pennsylvania School of Veterinary Medicine in Philadelphia, to investigate poly(ADP-ribose)-dependent chromatin remodeling events and epigenetic programming in the male germ line. During this time, I taught veterinary pharmacology, a course that I also co-organized. In August 2013, I joined the USU faculty as Associate Professor in the Animal, Dairy and Veterinary Sciences where I have been teaching and directing the VM7522 Pharmacology course in the joint School of Veterinary Medicine Program with Washington State University (WIMU).

There are undergraduate and graduate student research opportunities currently available in the lab – please contact me by email: Ralph Meyer. Take a look at the openings here.

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  • Course name: Fundamentals of Veterinary Pharmacology
    Course number (include any cross listings):  VM7522, Course Director
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Education and Research

  • Education
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    • Diplom (Biology) in Molecular Cell Biology, 1994, University of Kaiserslautern, Germany.
      Thesis: Methods of plant regeneration for Phaseolus vulgaris L and Agrobacterium mediated gene transfer.
    • Dr. rer. nat. (Ph.D.) in Molecular Toxicology, 1998, University of Kaiserslautern and DKFZ, Heidelberg, Germany. Dissertation: Inducible overexpression of human poly(ADP-ribose) polymerase in stably transfected mammalian cell cultures and its effects on the genetic stability of the cells“
    • Postdoc in Radiobiology/Molecular Pathology 1998-2001, University Hospital of Tuebingen, Germany.
      Research emphasis on X-ray induced cell signaling leading to egr-1 promoter activation in human glioma cells and development of novel viral vectors for gene therapy of heart diseases.
    • Research Scientist in Pharmacology/Toxicology, University of Arizona, and Niadyne Inc., Tucson, 2002-2005, investigating pharmacological targeting of poly(ADP-ribose) metabolism.
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  • Research Goals    
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    • My research interests are focused on spermatogenesis and the sperm chromatin biology relevant to male (in)fertility and epigenetic inheritance which is important to offspring health and disease in both, humans and animals.

      Mammalian sperm chromatin is epigenetically “programmed” to support embryonic development after fertilization. This epigenetic information the sperm carries consists of specific DNA methylation patterns, regulatory RNAs and residual histones with their posttranslational modifications, and all are venues that have the potential to regulate gene transcription in the embryo. Importantly, in mature mammalian sperm 85-99% (dependent on the species) of histones have been replaced by a different set of proteins (protamines) and only a subset of histones remain bound to strategically important domains of the genome, including regulatory regions of genes. We recently discovered that these remaining histones have a significant impact on early gene expression in embryos and found that their numbers and position can be changed by altering an environmentally regulated metabolic pathway, poly(ADP-ribose) metabolism (PAR), which changes gene expression in preimplantation embryos.

      Our data obtained from mouse models therefore support the amazing view that men are susceptible to environmental and dietary influences throughout their lifetime which change epigenetic programming of their sperm with potentially lasting consequences to their children.

      Based on our prior research, current projects in the laboratory are guided by the central question how genetic, environmental and dietary factors affect spermatogenesis and therefore chromatin integrity and sperm epigenetic programming:

      1. What is the nature of epigenetic changes (“epimutations”) that occur in males in response to nutritional factors and environmental toxins and what are the molecular mechanisms involved?
      2. How does a change in sperm histone retention cause differential gene expression during genome activation in preimplantation embryos?
      3. What are long-term consequences of sperm epimutations on embryonic and postnatal development, as well as adulthood?
      4. What are biomarkers of aberrant sperm chromatin development and programming?

      Addressing these questions, we are working with transgenic and pharmacological mouse models in the laboratory, using a diverse array of state-of-the-art techniques, such as chromatin IP (ChIP), next generation sequencing of DNA and RNA for global gene expression analyses, proteomics, fluorescence in situ hybridization (FISH), FACS, quantitative microscopic image analysis, histology and many methods related to reproductive biology such as IVF, ICSI, tissue and embryo culture, etc.

      Understanding molecular mechanisms of epigenetic inheritance through the male germ line will be helpful for the development of avoidance strategies and male “preconceptional” dietary supplements, which are our long-term goals to help children to be born healthier. This research is also of relevance to companion animals and animal production in agriculture.
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  • Peer Reviewed Research Articles
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    • Meyer-Ficca M.L., Scherthan H., Bürkle A., Meyer R.G .(2005). Poly(ADP-ribosyl)ation during chromatin remodeling steps in rat spermiogenesis. Chromosoma. 114(1):67-74. Epub 2005 Apr 19
    • Meyer R.G., Meyer-Ficca M.L., Whatcott C.J., Wang Z.Q., Jacobson M.K. (2007) Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity. Exp Cell Res 313(13):2920-36.
    • Meyer-Ficca M.L., Lonchar J.D., Credidio C., Ihara M., Li Y., Wang Z.Q., Meyer R.G. (2009) Disruption of Poly(ADP-Ribose) Homeostasis Affects Spermiogenesis and Sperm Chromatin Integrity in Mice. Biol Reprod 81(1):46-55. Epub Mar 4, 2009.
    • Meyer-Ficca M.L., Lonchar J.D., Ihara M., Meistrich M.L., Austin C.A., Min W., Wang Z.Q., Meyer R.G. (2011) Poly(ADP-ribose) metabolism is essential for proper nucleoprotein exchange during mouse spermiogenesis. Biol Reprod 84(2):218-28.
    • Meyer-Ficca M.L., Ihara M., Lonchar J.D., Meistrich M.L., Austin C.A., Meyer R.G. (2011) Poly(ADP-ribose) polymerases PARP1 and PARP2 modulate topoisomerase II beta (TOP2B) function during chromatin condensation in murine spermiogenesis. Biol Reprod 84(5):900-9.
    • Highlighted in Editorial: Ward W.S. (2011).Regulating DNA Supercoiling: Sperm Points the Way. Biol Reprod 84(5):841-3.
    • Meyer-Ficca M.L., Meyer, R.G. (2011) Genetic approaches to targeting multiple PARP genes in a mammalian genome. Methods in Molecular Biology, Methods Mol Biol. 2011;780:349-76.
    • Bryant, J. M., Meyer-Ficca M. L., Dang V. M., Berger S. L., Meyer R. G. (2013) Separation of Spermatogenic Cell Types using STA-PUT Velocity Sedimentation. Journal of Visual Experiments, J Vis Exp. 2013 Oct 9;(80).
    • Meyer-Ficca M. L., Lonchar J. D., Ihara M., Bader J. J., Meyer R. G. (2013) Alteration of poly(ADP-ribose) metabolism affects murine sperm nuclear architecture by impairing pericentric heterochromatin condensation. Chromosoma 122(4):319-35.
    • Ihara M, Meyer-Ficca ML, Leu NA, Rao S, Li F, Gregory BD; Zalenskaya IA, Schultz RM, Meyer RG (2014). Poly(ADP-ribose) metabolism regulates retention of inheritable sperm histones and modulates embryonic genome activation. *Authors contributed equally. PLoS Genet 10(5).
    • Highlighted in: Schubert C. (2014) World of Reproductive Biology: Histones Convey Information between Generations. Biol Reprod, published online before print May 14, 2014, doi: 10.1095/biolreprod.114.121467
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  • Book Chapters
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    • Meyer R.G., Meyer-Ficca M.L., Jacobson E.L., Jacobson M.K. (2004) Enzymes in poly(ADP-ribose) metabolism; bookchapter in: Burkle, A (ed): Poly(ADP-ribosyl)ation, Landes Bioscience, ISBN 1-58706-292-5
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  • Patents
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    • Bürkle A; Meyer R. (1998) Vectors and viruses for gene therapy, PCT/DE99/00647, German Cancer Research Center, Heidelberg. International Patent issued 2001.
    • Küpper J-H, Meyer R, Meyer-Ficca M, Kandolf R. Coxsackievirus B3 Vectorsystems for Gene Terapy. German patent application DE 199 39 095.9, priority August 18, 1999; International patent application PCT/EP00/07768.
    • Küpper J-H, Meyer R, Meyer-Ficca M, Kandolf R. Tumor-specific vector for Gene Terapy. German patent application DE 199 47 668.3, priority October 4, 1999; International patent application PCT/EP00/08921.
    • Küpper J-H, Meyer R, Kandolf R. Differentiation Eliciting Substances. German patent application DE 100 56 059.8, priority November 11, 2000; International patent application PCT/EP01/12660
    • Küpper J-H, Meyer R, Meyer-Ficca M, Kuhn A. Transient Immortalization. German patent application DE 101 52 972.4, priority October 18, 2001. International patent application PCT/EP02/11200.
    • (Patent assignees: 1: University Hospital of Tuebingen, Germany, 2-3: Heart BioSystems GmbH, Tuebingen, Germany)
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  • Financial Support    
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    • Current research in my lab is supported by a grant by the Utah Agricultural Experiment Station. Previous recent funding was provided by NIH grants R01 HD48837 and U54HD068157, a Michelson Grant in Reproductive Biology, and the Raymond Firestone Trust.
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Honors and Activities

  • Professional Society Memberships
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    • 2001-2002 European Society for Gene Therapy
    • 2003-2012 Member, American Association for Cancer Research, AACR
    • 2005- Member, German Society for DNA Repair Research, DGDR
    • 2007- Member, American Society for Andrology
    • 2009- Member, Society for the Study of Reproduction
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  • Awards
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    • 2002 NIH Ruth-Kirschstein-NRSA postdoctoral fellowship (T32, 2002-2004)
    • 2004 Special Recognition Award in Basic Science, American Association for Cancer Research,
      AACR Pathobiology of Cancer: The Edward A. Smuckler Memorial Workshop, Snowmass Village, Colorado
    • 2004 Travel Award, The 53rd Fujihara International Seminar, Tomakomai, Hokkaido, Japan, The Fujihara Foundation of Science
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