Ryan M. O'Connell, Ph.D.

Ryan M. O'Connell, Ph.D.

Assistant Professor of Pathology

 
Scholarly Emphasis: Function of noncoding RNAs in the immune system

Our laboratory is exploring the function of non-coding RNAs (including microRNAs) during inflammatory responses. Furthermore, we are investigating why disruptions in non-coding RNA expression or function is linked to human diseases such as autoimmunity and cancer.

Decades of research efforts have found vital roles for protein coding genes in the control of mammalian immune system development and function. Despite these advancements, many aspects of the immune system remain unresolved and are governed by complex regulatory networks. Non-coding (nc) RNAs make up a majority of the RNA molecules found in mammalian cells. However, ncRNAs have just recently been appreciated as experiments are starting to demonstrate that they are functionally important during normal physiology while also being implicated in human disease. Thus, ncRNAs are a promising new frontier in not only the field of immunology, but molecular biology in general.

Consequently, our research efforts have been focused on understanding the functional roles of miRNAs expressed in the immune system. Our previous studies identified one miRNA, called miR-155, as an inflammation-induced miRNA that promotes inflammatory responses. This is achieved through the repression of powerful protein regulators of immune system activation. Because some of these targets of miR-155 are established tumor suppressors, these findings have also unveiled miR-155 as an important link between inflammation and cancer.

While it is becoming quite clear that miRNAs are integral components of the molecular networks regulating immune system biology, the field is very new and thus the identities and specific functions of several immunologically relevant miRNAs and other ncRNAs remain a mystery. My research group will therefore be focused on investigating the importance of ncRNAs in two highly important areas of immune system biology including:

1) The regulation of hematopoietic stem cell (HSC) function during inflammation

2) The control of antigen specific inflammatory responses

Identifying and characterizing ncRNAs involved in these areas of study will be essential for the progress of basic science. Furthermore, this information may also lead to the identification of biomarkers and therapeutic molecular targets that can be used for the diagnosis and treatment of such disorders as cancer and autoimmunity.

Selected Publications

  • Zhou JL, Roa DS, Boldin MP, Taganov KD, O'Connell RM, Baltimore D. NF-κB dysregulation in miR-146a-deficient mice drives the development of myeloid malignancies as the mice age. Proc Natl Acad Sci USA. (2011) May 31;108(22):9184-9.
  • O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D.(2010). MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity, 33(4), 607-19.
  • O'Connell RM, Chaudhuri AA, Rao DS, Gibson WS, Balazs AB, Baltimore D. (2010). MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc Natl Acad Sci USA, 107(32), 14235-40.
  • Rao DS, O'Connell RM, Chaudhuri AA, Garcia-Flores Y, Geiger TL, Baltimore D. (2010). MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity, 33(1), 48-59.
  • O'Connell RM, Balazs AB, Rao DS, Kivork C, Yang L, Baltimore D. (2010). Lentiviral vector delivery of human interleukin-7 (hIL-7) to human immune system (HIS) mice expands T lymphocyte populations. PLoS ONE, 5(8), e12009.
  • O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D. (2009). Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA, 106(17), 7113-8.
  • Luo XM, Maarschalk E, O'Connell RM, Wang P, Yang L, Baltimore D. (2009). Engineering human hematopoietic stem/progenitor cells to produce a broadly neutralizing anti-HIV antibody after in vitro maturation to human B lymphocytes. Blood, 113(7), 1422-31.
  • O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, Paquette RL, Baltimore D. (2008). Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med, 205(3), 585-94.
  • O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. (2007). MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA, 104(5), 1604-9.
  • Miller LS, O'Connell RM, Gutierrez MA, Pietras EM, Shahangian A, Gross CE, Thirumala A, Cheung AL, Cheng G, Modlin RL. (2006). MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity, 24(1), 79-91.
  • O'Connell RM, Vaidya SA, Perry AK, Saha SK, Dempsey PW, Cheng G. (2005). Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1. J Immunol, 174(3), 1602-7.
  • Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O'Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P. (2004). LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell, 119(2), 299-309.
  • O'Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, Perry AK, Nguyen BO, Lane TF, Taniguchi T, Miller JF, Cheng G. (2004). Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med, 200(4), 437-45.
  • Doyle SE, O'Connell RM, Miranda GA, Vaidya SA, Chow EK, Liu PT, Suzuki S, Suzuki N, Modlin RL, Yeh WC, Lane TF, Cheng G. (2004). Toll-like receptors induce a phagocytic gene program through p38. J Exp Med, 199(1), 81-90.
  • Doyle S, Vaidya S, O'Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G. (2002). IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity, 17(3), 251-63.
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Honors and Awards

  • 2010: K99/R00 Career Development Award, NHLBI
  • 2006: Irvington Institute Fellowship Program of the Cancer Research Institute, Postdoctoral Fellowship

Professional Education

  • 2005, Ph.D. Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles
  • 2001, M.S. Biology, University of the Pacific
  • 1998, B.S. Biology, California Lutheran University