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    Jack L Leonard PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-6687
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentAnesthesiology and Perioperative Medicine

      InstitutionUMMS - School of Medicine
      DepartmentMicrobiology and Physiological Systems

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

        Jack Leonard is currently Professor of Microbiology and Physiological Systems at the University of Massachusetts Medical School. His research focuses on three areas: cancer biology, molecular endocrinology, and developmental neurobiology. Dr. Leonard graduated from the University of California at Berkeley with a Ph.D. in 1976.  From 1976 to 1979 he was a post-doctoral fellow at Boston University School of Medicine where his work served as the foundation for the field of hormone metabolism as a key component of thyroid hormone action.  Dr. Leonard joined the faculty of Harvard Medical School in 1980 where he continued his work in molecular endocrinology and hormone action.  In 1986 Dr. Leonard moved to the faculty at UMMS and was appointed Professor in 1990.

        He served as a member of the editorial boards of Endocrinology and the American Journal of Physiology.  He served on multiple National Institutes of Health Study Sections and most recently was a regular member of the Molecular Cellular Endocrinology Study Section and as Chair of ad hoc NIH study sections and NIH Biological and Physiology, NRSA Specific Emphasis Panels.  He was a reviewer for Veterans Administration Endocrine Review Panels.  He is a member of the Scientific Advisory Board Endocrine Disruptor Screening Program at the Environmental Protection Agency. Dr. Leonard has received numerous awards for his research including the Van Meter/Rorer Prize of the American Thyroid Association, a Visiting Professorship of Endocrinology at Erasmus University Medical School, Rotterdam Netherlands, and was named a Scholar of the Hyundai Hope on Wheels for Pediatric Cancer.

        Regulation of Cell Proliferation in Cancer

        My research program is focused on defining the cell signaling defects responsible for the hyper-proliferative state in cancer.  Using a vital regulator of cell proliferation discovered in the laboratory, we are delineating the signaling networks affected, characterizing the role intracellular trafficking on pathway regulation, and dissecting the functional domain(s) of the regulatory molecule.  This regulator (DKK3b) is missing in most cancers and is an intracellular variant originating from an internal transcriptional start site in the Dkk3 gene locus.  We use a board spectrum of contemporary tools of biology to address these fundamental questions.

         

        Mouse models to study the biology of the Dkk3 gene locus.  In collaboration with Dr. Scot Wolfe, we selectively disrupt expression from the internal start site of Dkk3 locus in both cultured cells and the mouse using engineered gene-editing nucleases (zinc finger, TALEN, and CRISPR/Cas9) and homologous recombination.  These studies revealed, for the first time, the vital nature of the Dkk3 gene locus.  These powerful gene-editing platforms provide the means to study individual gene products originating from a single gene locus.  Importantly, selective loss of DKK3b results in an embryonic lethal pre-implantation defect and contrasts sharply with the viable, fertile phenotype generated by selective loss of the other Dkk3 gene product.  The molecular events responsible for disruption of embryogenesis is under study.

         

        Characterization of the functional domains of DKK3b.  We use progressive, nested truncation/deletion mutants, alanine-scanning mutagenesis, isoform domain swaps, and rationale design to define and modify the functional domains of this important regulator of cell proliferation.  Multiple signaling pathway reporter cell lines have been engineered in the laboratory that provide a powerful platform to detail the specific function of individual protein domains.  We continue to refine our understanding of the specificity and selectivity of individual functional domains of DKK3b to more broadly predict the molecular events capable of targeting individual signaling pathways.

         

        Cell Biology of DKK3b.  DKK3b shuttles rapidly between the cell periphery and the peri-nuclear space using myosin motors and actin fibers, and the role this shuttling process plays in the modulation of signaling pathways is under study.  Using both dominant negative inhibitors, cell penetrating peptides/proteins, motor inhibitors and gene editing knockout, we are systematically detailing the number and function of individual components in this trafficking network.

         

        Xenograft Models of Human Cancer.  In collaboration with Drs. Dale Greiner, Giles Whalen, Bruce Woda and Karl Simin we are collaborating in the development of cancer Avatars using the immune incompetent mouse model developed by Drs. Greiner and Leonard Schultz and patient derived tumor tissue.  Orthotopic implants of human pancreatic, ovarian, lymphoma and appendiceal cancer have been developed for study and provide the opportunity to study both tumor biology and the interactions between the patients immune system and their tumor in a model system.  We continue to refine this tumor model for use in evaluation of new therapeutic strategies for cancer treatment.



        Rotation Projects

        Potential Rotation Projects

        1. Real-time imaging of synaptic vesicle recycling will be done using cultured cerebellar granule neurons, dynamic confocal microscopy, vesicle specific fluorescent dyes, a cohort of GFP-tagged SV marker proteins. The student will learn contemporary techniques in cell and molecular neurobiology.


        2. In vitro propagated cerebellar progenitor cells isolated from a family of thyroid hormone receptor mutants will be implanted into normal neonatal mice and the developmental fate of the implanted cells characterized. The student will learn immunocytochemistry, FACS analysis, and transcript profiling using Affymetrix chip technology.


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Mercado-Lubo R, Zhang Y, Zhao L, Rossi K, Wu X, Zou Y, Castillo A, Leonard J, Bortell R, Greiner DL, Shultz LD, Han G, McCormick BA. A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. Nat Commun. 2016; 7:12225.
          View in: PubMed
        2. Davis PJ, Goglia F, Leonard JL. Nongenomic actions of thyroid hormone. Nat Rev Endocrinol. 2016 Feb; 12(2):111-21.
          View in: PubMed
        3. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010 Apr; 31(2):139-70.
          View in: PubMed
        4. Farwell AP, Leonard JL. Effect of methyl iodide on deiodinase activity. Inhal Toxicol. 2009 May; 21(6):497-504.
          View in: PubMed
        5. Leonard JL. Non-genomic actions of thyroid hormone in brain development. Steroids. 2008 Oct; 73(9-10):1008-12.
          View in: PubMed
        6. Davis PJ, Leonard JL, Davis FB. Mechanisms of nongenomic actions of thyroid hormone. Front Neuroendocrinol. 2008 May; 29(2):211-8.
          View in: PubMed
        7. Simpson GI, Leonard DM, Leonard JL. Identification of the key residues responsible for the assembly of selenodeiodinases. J Biol Chem. 2006 May 26; 281(21):14615-21.
          View in: PubMed
        8. Farwell AP, Dubord-Tomasetti SA, Pietrzykowski AZ, Leonard JL. Dynamic nongenomic actions of thyroid hormone in the developing rat brain. Endocrinology. 2006 May; 147(5):2567-74.
          View in: PubMed
        9. Alkemade A, Friesema EC, Unmehopa UA, Fabriek BO, Kuiper GG, Leonard JL, Wiersinga WM, Swaab DF, Visser TJ, Fliers E. Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus. J Clin Endocrinol Metab. 2005 Jul; 90(7):4322-34.
          View in: PubMed
        10. Leonard JL, Simpson G, Leonard DM. Characterization of the protein dimerization domain responsible for assembly of functional selenodeiodinases. J Biol Chem. 2005 Mar 25; 280(12):11093-100.
          View in: PubMed
        11. Farwell AP, Dubord-Tomasetti SA, Pietrzykowski AZ, Stachelek SJ, Leonard JL. Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3',5'-triiodothyronine. Brain Res Dev Brain Res. 2005 Jan 1; 154(1):121-35.
          View in: PubMed
        12. Dobson JG, Fray J, Leonard JL, Pratt RE. Molecular mechanisms of reduced beta-adrenergic signaling in the aged heart as revealed by genomic profiling. Physiol Genomics. 2003 Oct 17; 15(2):142-7.
          View in: PubMed
        13. Diano S, Leonard JL, Meli R, Esposito E, Schiavo L. Hypothalamic type II iodothyronine deiodinase: a light and electron microscopic study. Brain Res. 2003 Jun 20; 976(1):130-4.
          View in: PubMed
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