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Ryan O'Connell

Associate Professor of Pathology

Ryan O'Connell

B.S. California Lutheran University

Ph.D. University of California, Los Angeles

Research

References

ryan.oconnell@path.utah.edu

Ryan O'Connell's Lab Page

Ryan O'Connell's PubMed Literature Search

 

Molecular Biology Program

Noncoding RNAs, Inflammation, and Cancer

Research

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.

References

  1. Soto R, Petersen C, Novis CL, Kubinak JL, Bell R, Stephens WZ, Lane TE, Fujinami RS, Bosque A, O'Connell RM, Round JL. Microbiota promotes systemic T cell survival through suppression of an apoptotic factor. Proc Natl Acad Sci. 2017 May 23;114(21):5497-5502.

  2. Wallace JA, Kagele DA, Eiring AM, Kim CN, Hu R, Runtsch MC, Alexander M, Huffaker TB, Lee SH, Patel AB, Mosbruger TL, Voth W, Rao DS, Miles RR, Round JL, Deininger MW, O'Connell RM. miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response. Blood. 2017 Jun 8;129(23):3074-3086.

  3. Chiaro T, Soto R, Stephens, WZ, Kubinak, JL, Petersen, C, Gogokhia L, Bell R, Delgado JC, Cox J, Voth W, Brown J, Stillman D, O’Connell RM, Tebo A and Round JL. A member of the mycobiota modulates host metabolism to increase intestinal permeability and disease. Science Translational Medicine. 2017 Mar 8;9(380).

  4. Dickey L, Worne C, Glover J, Lane T and O’Connell RM. MicroRNA-155 enhances T cell trafficking and antiviral effector function in a model of coronavirus-induced neurologic disease. Journal of Neuroinflammation. 2016 Sep 7;13(1):240.

  5. Wallace J, Hu R, Mosbruger TL, Dahlem TJ, Stephens WZ, Rao DS, Round JL, O'Connell RM. Genome-Wide CRISPR-Cas9 Screen Identifies MicroRNAs That Regulate Myeloid Leukemia Cell Growth. PLoS One. 2016 Apr 15;11(4):e0153689.
  6. Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, Bell R, Ajami NJ, Petrosino JF, Morrison L, Potts WK, Jensen PE, O'Connell RM, Round JL. MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun. 2015 Oct 23;6:8642.
  7. Runtsch MC, Hu R, Alexander M, Wallace J, Kagele D, Petersen C, Valentine JF, Welker NC, Bronner MP, Chen X, Smith DP, Ajami NJ, Petrosino JF, Round JL, O'Connell RM. MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis. Oncotarget. 2015 Oct 6;6(30):28556-72.
  8. Alexander M, O'Connell RM. Noncoding RNAs and chronic inflammation: Micro-managing the fire within. Bioessays. 2015 Sep;37(9):1005-15. Review.
  9. Huffaker TB, O'Connell RM. miR-155-SOCS1 as a Functional Axis: Satisfying the Burden of Proof. Immunity. 2015 Jul 21;43(1):3-4.
  10. Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, Seabra MC, Round JL, Ward DM, O'Connell RM. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 2015 Jun 18;6:7321.
  11. O'Connell RM. Endogenous miR-29a regulates HSC function in mammals. Blood. 2015 Apr 2;125(14):2180-1.
  12. Kubinak JL, Petersen C, Stephens WZ, Soto R, Bake E, O'Connell RM, Round JL.  MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe. 2015 Feb 11;17(2):153-63.
  13. Hu R, Kagele DA, Huffaker TB, Runtsch MC, Alexander M, Liu J, Bake E, Su W, Williams MA, Rao DS, Möller T, Garden GA, Round JL, O'Connell RM. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity. 2014 Oct 16;41(4):605-19.
  14. Lochhead RB, Ma Y, Zachary JF, Baltimore D, Zhao JL, Weis JH, O'Connell RM, Weis JJ. MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog. 2014 Jun 26;10(6):e1004212.
  15. Zhao JL, Ma C, O'Connell RM, Mehta A, DiLoreto R, Heath JR, Baltimore D. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell. 2014 Apr 3;14(4):445-59.
  16. Zhao JL, Rao DS, O'Connell RM, Garcia-Flores Y, Baltimore D. MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice. Elife. 2013 May 21;2:e00537.
  17. Hu R, Huffaker TB, Kagele DA, Runtsch MC, Bake E, Chaudhuri AA, Round JL, O'Connell RM. MicroRNA-155 Confers Encephalogenic Potential to Th17 Cells by Promoting Effector Gene Expression. J Immunol. 2013 Jun 15;190(12):5972-80.
  18. Hu R, Wallace J, Dahlem TJ, Grunwald DJ, O'Connell RM. Targeting human microRNA genes using engineered Tal-effector nucleases (TALENs). PLoS One. 2013 May 7;8(5):e63074.
  19. Hu R, O'Connell RM. MicroRNA control in the development of systemic autoimmunity. Arthritis Res Ther. 2013 Jan 25;15(1):202.
  20. Huffaker TB, Hu R, Runtsch MC, Bake E, Chen X, Zhao J, Round JL, Baltimore D, O'Connell RM. Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep. 2012 Dec 27;2(6):1697-709.
  21. Hu R, O'Connell RM. MiR-23b is a safeguard against autoimmunity. Nat Med. 2012 Jul 6;18(7):1009-10.
  22. O'Connell RM. MicroRNAs function on a new level. Blood. 2012 Apr 26;119(17):3875-6.
  23. Chaudhuri AA, So AY, Mehta A, Minisandram A, Sinha N, Jonsson VD, Rao DS, O'Connell RM, Baltimore D. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A. Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4233-8.
  24. O'Connell RM, Baltimore D. MicroRNAs and hematopoietic cell development. Curr Top Dev Biol. 2012;99:145-74.
  25. O'Connell RM, Rao DS, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol. 2012;30:295-312.
  26. Chaudhuri AA, So AY, Sinha N, Gibson WS, Taganov KD, O'Connell RM, Baltimore D. MicroRNA-125b potentiates macrophage activation. J Immunol. 2011 Nov 15;187(10):5062-8.
  27. O'Connell RM, Zhao JL, Rao DS. MicroRNA function in myeloid biology. Blood. 2011 Sep 15;118(11):2960-9.
  28. Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM, Baltimore D. NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9184-9.
  29. Pietras EM, Miller LS, Johnson CT, O'Connell RM, Dempsey PW, Cheng G. A MyD88-dependent IFNγR-CCR2 signaling circuit is required for mobilization of monocytes and host defense against systemic bacterial challenge. Cell Res. 2011 Jul;21(7):1068-79.
  30. O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010 Oct 29;33(4):607-19.
  31. O'Connell RM, Chaudhuri AA, Rao DS, Gibson WS, Balazs AB, Baltimore D. MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14235-40.
  32. Rao DS, O'Connell RM, Chaudhuri AA, Garcia-Flores Y, Geiger TL, Baltimore D. MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity. 2010 Jul 23;33(1):48-59.
  33. O'Connell RM, Balazs AB, Rao DS, Kivork C, Yang L, Baltimore D. Lentiviral vector delivery of human interleukin-7 (hIL-7) to human immune system (HIS) mice expands T lymphocyte populations. PLoS One. 2010 Aug 6;5(8):e12009.
  34. O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7113-8.
  35. Hwang S, Kim KS, Flano E, Wu TT, Tong LM, Park AN, Song MJ, Sanchez DJ, O'Connell RM, Cheng G, Sun R. Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response. Cell Host Microbe. 2009 Feb 19;5(2):166-78.
  36. Luo XM, Maarschalk E, O'Connell RM, Wang P, Yang L, Baltimore D. Engineering human hematopoietic stem/progenitor cells to produce a broadly neutralizing anti-HIV antibody after in vitro maturation to human B lymphocytes. Blood. 2009 Feb 12;113(7):1422-31.
  37. O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, Paquette RL, Baltimore D. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008 Mar 17;205(3):585-94.

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Last Updated: 6/19/17