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Richard R. Hardy, PhD

R Hardy, PhD
About

Professor

Senior Member

Member, Faculty of 1000, Leukocyte Development Section

    Research Program

    Structure of the pre-B cell receptor (pre-BCR)
    Pre-BCR formation results in a proliferative burst
    Progression of pro-B cells (blue) to pre-B (red) requires the pre-BCR

     

    Education, Training & Credentials

    Educational Background

    • Postdoctoral studies, Molecular Immunology, Stanford medical School, 1981-1984
    • PhD, Biochemistry, California Institute of Technology, Pasadena, CA, 1980
    • BS, Chemistry, Illinois Institute of Technology, Chicago, IL, 1974

    Honors & Awards

    • Chemistry Department Achievement Award, Illinois Institute of Technology
    • Academic Achievement Award, Illinois Institute of Technology
    • Herbert Newby McCoy Award, Department of Chemistry, California Institute of Technology
    • American Cancer Society, California Division, Junior Fellowship (3/82-3/84)
    • American Cancer Society, California Division, Senior Fellowship (3/84-11/84)
    Research Profile

    Research Program

    Research Interests

    • Regulation of B cell development in fetal liver and bone marrow
    • Fetal B cell development mediated by Lin28b/Let-7 and Arid3a
    • Role of pre-BCR and BCR in selecting B cells into functionally distinct B cell subsets 

    Lab Overview

    Fetal and Adult B Lymphocyte Differentiation

    B lymphocyte development in mouse, as in humans, takes place in the fetal liver before birth and shifts shortly thereafter to the bone marrow, where it continues throughout life. The generation of B cells is a highly ordered process, orchestrated by a number of transcription factors that regulate expression of a set of lymphoid and B lineage specific genes at well-defined developmental stages. During this process, immunoglobulin (Ig) heavy chain D-to-J rearrangements in pro-B cells precede V-to-DJ rearrangements that eventually yield functional heavy chain protein in pre-B cells. In pre-B cells, this Ig heavy chain protein associates with B lineage specific surrogate light chain components to form a pre-BCR. This signals events required for development to later stages where Ig light chain rearrangement takes place and is expressed. Ig light chain becomes associated with heavy chain, allowing a complete Ig molecule, the BCR, to be expressed on the surface of a newly formed B cell.

    The interests of my laboratory focus on three areas related to this process: 1) elucidating the stage(s) and molecular/cellular interactions taking place as B cell precursors become progressively restricted to the B lineage; 2) determining the role of Ig heavy chain VDJ structures in guiding B cell development; and 3) comparing fetal and adult B cell development, particularly as related to the preferential generation of autoreactive malignant-prone CD5+ ("B-1") B cells during embryogenesis. We utilize transgenesis and knockout/knockin mice to study these issues. We are also investigating the peripheral maturation of B cells in spleen and have initiated a project to mark B cells in the zebrafish. Recently we have identified the transcription factor Arid3a as key in mediating fetal B cell development. We are now studying whether this fetal versus adult B cell developmental switch also occurs in humans, and have generate preliminary data suggesting that it does.

    People

    Yue-Sheng Li, PhD

    Staff Scientist

    Room: W305
    215-728-3174

    Susan Shinton, BS

    Scientific Associate

    Room: R385
    215-728-2463
    Extramural Affiliations

    Adjunct Professor, Thomas Jefferson University Department of Microbiology and Immunology

    Publications

    Selected Publications

    Zhou, Y., Li, Y.-S., Bandi, S.R., Tang, L., Shinton, S.A., Hayakawa, K., and Hardy, R.R. Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a. J. Exp. Med. 212:569-580, 2015.  PMC4387290  PMID25753579 PubMed

    Ichikawa, D., M. Asano, S.A. Shinton, J. Brill-Dashoff, A.M. Formica, A. Velcich, R.R. Hardy, and K. Hayakawa. Natural anti-intestinal goblet cell autoantibody production from marginal zone B cells. J. Immunol 2194:606-614, 2015.  PMC4282382  PMID25480561 PubMed

    Shukla, V., S. Ma, R.R. Hardy, S.S. Joshi, and R. Lu. A role for IRF4 in the development of CLL. Blood  122:2848-2855, 2013.  PMC3798999  PMID23926303 PubMed

    Cooper C.L., Hardy R.R., Reth M., and Desiderio, S.  Non-cell-autonomous hedgehog signaling promotes murine B lymphopoiesis from hematopoietic progenitors. Blood 119:5438-5448, 2012.  PMC3369680  PMID22517907 PubMed

    Painter, M.W., Davis, S., Hardy, R.R., Mathis, D., and Benoist, C.  Transcriptomes of the B and T Lineages Compared by Multiplatform Microarray Profiling. J Immunol 186:3047-3057, 2011.  PMC3140206  PMID21307297 PubMed

    Amin, R.H., D. Cado, H. Nolla, D. Huang, S.A. Shinton, Y. Zhou, R.R. Hardy, and M.S. Schlissel. Biallelic, ubiquitous transcription from the distal germline Ig{kappa} locus promoter during B cell development. Proc Natl Acad Sci U S A 106:522-527, 2009.  PMC2626736  PMID19116268 PubMed

    Kadariya, Y., Yin, B., Tang, B., Shinton, S.A., Quinlivan,  E.P., Hua, X., Klein-Szanto, A., Al-Saleem, T.I., Bassing, C.H., Hardy, R.R., Kruger, W.D.  Mice heterozygous for germline mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma.  Cancer Res. 69:5961-5969, 2009.  PMC2757012  PMID19567676 PubMed

    Zhang, H., S. Rosenberg, F. J. Coffey, Y. W. He, T. Manser, R. R. Hardy and J. Zhang.  A role for cFLIP in B cell proliferation and stress MAPK regulation. J Immunol 182: 207-215, 2009.  PMC2720129  PMID19109151 PubMed

    Rowley, B.M., Tang, L., Shinton, S.A., Hayakawa, K., and Hardy, R.R..  Autoreactive B-1 B Cells: Constraints on Natural Autoantibody B Cell Antigen Receptors.  Journal of Autoimmunity, 29:236-245, 2007.  PMC2096705  PMID17889506 PubMed

    Kitaura, Y., Jang, I.K., Wang, Y., Han, Y.C., Inazu, T., Cadera, E.J., Schlissel, M., Hardy, R.R., and Gu, H. Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity 26:567-578, 2007.  PMC1948079  PMID17493844 PubMed

    Rumfelt, L.L., Zhou, Y., Rowley, B.M., Shinton, S.A., and Hardy, R.R.   Lineage specification and plasticity in CD19– early B cell precursors.  J. Exp. Med. 203: 675-687, 2006.  PMC2118241  PMID16505143 PubMed

    Wen, L., Brill-Dashoff, J., Shinton, S. A., Asano, M., Hardy, R. R., and Hayakawa, K. Evidence of marginal-zone B cell- positive selection in spleen. Immunity 23, 297-308, 2005. PubMed

    Wen, L., Shinton, S.A., Hardy, R.R., Hayakawa, K.  Association of B-1 B cells with follicular dendritic cells in spleen.  J. Immunol. 174:6918-6926, 2005.  PMID16169502 PubMed

    Maier H, Ostraat R, Gao H, Fields S, Shinton SA, Medina KL, Ikawa T, Murre C, Singh H, Hardy RR, Hagman J. Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription. Nat Immunol. 2004 5:1069-1077.  PMID1536186 PubMed

    Hayakawa K, Asano M, Shinton SA, Gui M, Wen LJ, Dashoff J, Hardy RR. Positive selection of anti-Thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. J Exp Med. 2003 197:87-99. PMC2193793  PMID12515816 PubMed

    Additional Publications

    My NCBI