Research Summary

My laboratory studies tyrosine kinase based signal transduction in innate immune cells. Our general approach involves examination of innate immune function in knockout mice lacking various members of the Src-family or Syk family of tyrosine kinases. Many of these studies also involve use of mice lacking these kinases in specific hematopoietic lineages, such as neutrophils, macrophages or DCs, generated through Cre/Lox technology. We have also used this approach to study other tyrosine kinases (Pyk2/Fak) and intracellular signaling molecules (WASp, STIM1) in innate immune cells. Our major findings have illuminated the function of Src-family and Syk kinases in leukocyte integrin signaling—loss of these kinases results in significant defects in inflammatory and host defense functions mediated by integrins. We have found that leukocyte integrin signaling utilizes the same intracellular pathways initiated by classical immunoreceptors (e.g., FcγRs) by co-opting ITAM-containing adapter proteins. We have also demonstrated the important ways these kinases regulate innate immune cells in the setting of autoimmune and inflammatory diseases, using the Lyn kinase-deficient model. Ongoing studies also involve examination of tyrosine phosphatases (mainly SHP-1) in the counter regulation tyrosine kinases, especially in the setting of hematopoietic malignancy, as well as studies of calcium signaling proteins, using mice lacking these genes specifically in myeloid lineage cells.

Research Funding

  • February 1, 2015 - January 31, 2021 - Regulation of Innate Immune Signaling by Lyn Kinase , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI113272
  • July 1, 2005 - January 31, 2019 - Mechanisms of Neutrophil Activation , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI065495
  • August 1, 2000 - January 31, 2018 - Signaling by Cytoplasmic Tyrosine Kinases in Leukocytes , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI068150
  • July 15, 2008 - June 30, 2014 - Innate immune regulation of inflammation and adaptive immunity , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01AI078869
  • September 30, 2005 - August 31, 2011 - Transfusion and Lung Injury , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P50HL081027
  • June 21, 2009 - June 29, 2009 - Signal Transduction in the Immune System-FASEB Summer Conference , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13AI084313
  • August 15, 2004 - July 31, 2008 - Proximal Signaling Events in Leukocyte Integrin Function , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R03TW006831
  • June 1, 2007 - May 31, 2008 - FASEB Summer Conference on Signal Transduction in the Immune System , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13AI074219
  • February 1, 1996 - December 31, 2006 - TRANSFUSION BIOLOGY AND MEDICINE , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P50HL054476
  • July 1, 2001 - June 30, 2006 - Signaling by Cytoplasmic Tyrosine Kinases in Leukocytes , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DK058066
  • August 15, 1995 - July 31, 2001 - MURINE MODELS TO INVESTIGATE THE HEMATOLOGIC SYSTEM , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01DK050267

Education

Stanford University, B.S., 1979, Biology
The Johns Hopkins University School of Medicine, M.D., 1986, Medicine
The Johns Hopkins University School of Medicine, Ph.D., 1986, Biochemistry/Molecular Biology

Honors & Awards

  • 1979
    Phi Beta Kappa, Stanford University
  • 1979-86
    Medical Scientist Training Program Scholarship, The Johns Hopkins University School of Medicine
  • 1986
    Alpha Omega Alpha, The Johns Hopkins University School of Medicine
  • 1990
    Diplomat of American Board of Internal Medicine
  • 1992
    Awardee Howard Hughes Physician Scientist Training Fellowship
  • 1997
    Awardee American Society of Hematology Junior Faculty Scholar Award
  • 2000
    Awardee Stewart Family Trust Scholar Award
  • 2000
    Awardee Leukemia Research Foundation New Investigator Award
  • 2001
    Awardee Leukemia/Lymphoma Society Scholar Award
  • 2003
    UCSF Immunology Program Annual Student-selected Faculty Speaker
  • 2003
    Appointed Associate Director, UCSF M.D.-Ph.D. (MSTP) Program
  • 2005
    Federation of American Societies for Experimental Biology (FASEB) - elected organizer 2007 meeting

Selected Publications

  1. Futosi K, Németh T, Horváth ÁI, Abram CL, Tusnády S, Lowell CA, Helyes Z, Mócsai A. Myeloid Src-family kinases are critical for neutrophil-mediated autoinflammation in gout and motheaten models. J Exp Med. 2023 07 03; 220(7).  View on PubMed
  2. Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu D, Zamecnik C, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, DeRisi JL. Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities. bioRxiv. 2023 Apr 07.  View on PubMed
  3. Hu C, Priceputu E, Cool M, Chrobak P, Bouchard N, Forestier C, Lowell CA, Bénichou S, Hanna Z, Royal V, Jolicoeur P. NEF-Induced HIV-Associated Nephropathy Through HCK/LYN Tyrosine Kinases. Am J Pathol. 2023 06; 193(6):702-724.  View on PubMed
  4. Costa S, Bevilacqua D, Caveggion E, Gasperini S, Zenaro E, Pettinella F, Donini M, Dusi S, Constantin G, Lonardi S, Vermi W, De Sanctis F, Ugel S, Cestari T, Abram CL, Lowell CA, Rodegher P, Tagliaro F, Girolomoni G, Cassatella MA, Scapini P. Neutrophils inhibit γδ T cell functions in the imiquimod-induced mouse model of psoriasis. Front Immunol. 2022; 13:1049079.  View on PubMed
  5. Thomas K, Zondler L, Ludwig N, Kardell M, Lüneburg C, Henke K, Mersmann S, Margraf A, Spieker T, Tekath T, Velic A, Holtmeier R, Hermann J, Jankowski V, Meersch M, Vestweber D, Westphal M, Roth J, Schäfers MA, Kellum JA, Lowell CA, Rossaint J, Zarbock A. Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells. JCI Insight. 2022 Nov 08; 7(21).  View on PubMed
  6. Poh AR, O'Brien M, Chisanga D, He H, Baloyan D, Traichel J, Dijkstra C, Chopin M, Nutt S, Whitehead L, Boon L, Parkin A, Lowell C, Pajic M, Shi W, Nikfarjam M, Ernst M. Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis. Cell Rep. 2022 10 11; 41(2):111479.  View on PubMed
  7. Poh AR, Love CG, Chisanga D, Steer JH, Baloyan D, Chopin M, Nutt S, Rautela J, Huntington ND, Etemadi N, O'Brien M, O'Keefe R, Ellies LG, Macri C, Mintern JD, Whitehead L, Gangadhara G, Boon L, Chand AL, Lowell CA, Shi W, Pixley FJ, Ernst M. Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy. Sci Adv. 2022 Jun 24; 8(25):eabl7882.  View on PubMed
  8. Lowell CA. Hyperuricemia reduces neutrophil function. Blood. 2022 06 09; 139(23):3354-3356.  View on PubMed
  9. Mianmian Yin, Jennifer A Smith, Marissa Chou, Jackie Chan, Yongmei Hu, Clifford A Lowell, Douglas B Gould, Mark S Anderson, Anthony L DeFranco. Autoantigen specific T-cell receptor induces organ-specific autoimmunity by escaping T cell negative selection. The Journal of Immunology. 2022 May 1; 208(1_Supplement):104.02-104.02.  View on PubMed
  10. Mianmian Yin, Kamir J Hiam, Irina Proekt, Jackie Chan, Yongmei Hu, Clifford A Lowell, Douglas B Gould, Matthew Spitzer, Mark S Anderson, Anthony L DeFranco. Development of uveitis in a mouse model of spontaneous autoimmunity correlates with frequency of autoantigen-specific regulatory T cells. The Journal of Immunology. 2022 May 1; 208(1_Supplement):44.07-44.07.  View on PubMed
  11. Brian BF, Sauer ML, Greene JT, Senevirathne SE, Lindstedt AJ, Funk OL, Ruis BL, Ramirez LA, Auger JL, Swanson WL, Nunez MG, Moriarity BS, Lowell CA, Binstadt BA, Freedman TS. A dominant function of LynB kinase in preventing autoimmunity. Sci Adv. 2022 Apr 22; 8(16):eabj5227.  View on PubMed
  12. Margraf A, Lowell CA, Zarbock A. Neutrophils in acute inflammation: current concepts and translational implications. Blood. 2022 04 07; 139(14):2130-2144.  View on PubMed
  13. McCreedy DA, Abram CL, Hu Y, Min SW, Platt ME, Kirchhoff MA, Reid SK, Jalufka FL, Lowell CA. Spleen tyrosine kinase facilitates neutrophil activation and worsens long-term neurologic deficits after spinal cord injury. J Neuroinflammation. 2021 Dec 24; 18(1):302.  View on PubMed
  14. Hua-Xin Gao, Eleanor Fraser, Mario Merlini, Huimin Geng, Lingjing Chen, Ming Lu, Yasmin Moshfegh, Joseph Cleveland, Jae Ryu, Jigyasa Sharma, David A. Solomon, Katerina Akassoglou, Clifford Lowell, James L. Rubenstein. Regulation of CNS Lymphoma Progression By the Myeloid Microenvironment. Blood. 2021 Nov 5; 138(Supplement 1):448-448.  View on PubMed
  15. Khan N, Hu Y, Lowell CA, Rothstein TL. Signal Integration by Translocation and Phosphorylation of PKCδ in the B Cell Alternate Pathway. J Immunol. 2021 11 01; 207(9):2288-2296.  View on PubMed
  16. Priceputu E, Cool M, Bouchard N, Caceres-Cortes JR, Lowell CA, Hanna Z, Jolicoeur P. HIV-1 Nef Induces Hck/Lyn-Dependent Expansion of Myeloid-Derived Suppressor Cells Associated with Elevated Interleukin-17/G-CSF Levels. J Virol. 2021 08 10; 95(17):e0047121.  View on PubMed
  17. Rutsch N, Chamberlain CE, Dixon W, Spector L, Letourneau-Freiberg LR, Lwin WW, Philipson LH, Zarbock A, Saintus K, Wang J, German MS, Anderson MS, Lowell CA. Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation. Diabetes Care. 2021 08; 44(8):1816-1825.  View on PubMed
  18. CHESTER CHAMBERLAIN, NIKLAS RUTSCH, WESLEY DIXON, LISA R. LETOURNEAU-FREIBERG, LOUIS H. PHILIPSON, MICHAEL GERMAN, MARK S. ANDERSON, CLIFFORD A. LOWELL. 1126-P: Activating SKAP2 Mutation Linked to Diabetes with Multiple Autoimmune and Inflammatory Conditions. Diabetes. 2021 Jun 21; 70(Supplement 1):1126-p.  View on PubMed
  19. Trivedi A, Tercovich KG, Casbon AJ, Raber J, Lowell C, Noble-Haeusslein LJ. Neutrophil-specific deletion of Syk results in recruitment-independent stabilization of the barrier and a long-term improvement in cognitive function after traumatic injury to the developing brain. Neurobiol Dis. 2021 09; 157:105430.  View on PubMed
  20. Okubo K, Brenner MD, Cullere X, Saggu G, Patchen ML, Bose N, Mihori S, Yuan Z, Lowell CA, Zhu C, Mayadas TN. Inhibitory affinity modulation of FcγRIIA ligand binding by glycosphingolipids by inside-out signaling. Cell Rep. 2021 05 18; 35(7):109142.  View on PubMed

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