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, 2020 - Regulation of Innate Immune Signaling by Lyn Kinase, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R01AI113272
  • August 1, 2000 - January 31, 2017 - Signaling by Cytoplasmic Tyrosine Kinases in Leukocytes, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R01AI068150
  • July 15, 2008 - June 30, 2013 - Innate immune regulation of inflammation and adaptive immunity, Co-Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: P01AI078869
  • September 30, 2005 - August 31, 2011 - Transfusion and Lung Injury, Co-Investigator. Sponsor: NIH/NHLBI, Sponsor Award ID: P50HL081027

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. 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
  2. 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
  3. Margraf A, Lowell CA, Zarbock A. Neutrophils in acute inflammation - current concepts and translational implications. Blood. 2021 Oct 08.  View on PubMed
  4. 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 Nov 01; 207(9):2288-2296.  View on PubMed
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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 May 18; 35(7):109142.  View on PubMed
  10. Romain Ballet, Martin Brennan, Carolin Brandl, Ningguo Feng, Jeremy Berri, Julian Cheng, Borja Ocón, Amin Alborzian Deh Sheikh, Alex Marki, Yuhan Bi, Clare Abram, Clifford Lowell, Takeshi Tsubata, Harry Greenberg, Matthew Macauley, Klaus Ley, Lars Nitschke, Eugene Butcher. A CD22-Shp1 phosphatase axis controls integrin ß 7 display and B cell function in mucosal immunity. The FASEB Journal. 2021 May 14; 35(S1).  View on PubMed
  11. Ballet R, Brennan M, Brandl C, Feng N, Berri J, Cheng J, Ocón B, Alborzian Deh Sheikh A, Marki A, Bi Y, Abram CL, Lowell CA, Tsubata T, Greenberg HB, Macauley MS, Ley K, Nitschke L, Butcher EC. A CD22-Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity. Nat Immunol. 2021 03; 22(3):381-390.  View on PubMed
  12. Kangelaris KN, Clemens R, Fang X, Jauregui A, Liu T, Vessel K, Deiss T, Sinha P, Leligdowicz A, Liu KD, Zhuo H, Alder MN, Wong HR, Calfee CS, Lowell C, Matthay MA. A neutrophil subset defined by intracellular olfactomedin 4 is associated with mortality in sepsis. Am J Physiol Lung Cell Mol Physiol. 2021 05 01; 320(5):L892-L902.  View on PubMed
  13. Cleary SJ, Kwaan N, Tian JJ, Calabrese DR, Mallavia B, Magnen M, Greenland JR, Urisman A, Singer JP, Hays SR, Kukreja J, Hay AM, Howie HL, Toy P, Lowell CA, Morrell CN, Zimring JC, Looney MR. Complement activation on endothelium initiates antibody-mediated acute lung injury. J Clin Invest. 2020 11 02; 130(11):5909-5923.  View on PubMed
  14. Myers DR, Abram CL, Wildes D, Belwafa A, Welsh AMN, Schulze CJ, Choy TJ, Nguyen T, Omaque N, Hu Y, Singh M, Hansen R, Goldsmith MA, Quintana E, Smith JAM, Lowell CA. Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity. Front Immunol. 2020; 11:576310.  View on PubMed
  15. Grimes D, Johnson R, Pashos M, Cummings C, Kang C, Sampedro GR, Tycksen E, McBride HJ, Sah R, Lowell CA, Clemens RA. ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense. Proc Natl Acad Sci U S A. 2020 09 29; 117(39):24403-24414.  View on PubMed
  16. Liang J, Zhang JJ, Huang HI, Kanayama M, Youssef N, Jin YJ, Reyes EY, Abram CL, Yang S, Lowell CA, Wang D, Shao L, Shinohara ML, Zhang JY, Hammer GE. The Ubiquitin-Modifying Enzyme A20 Terminates C-Type Lectin Receptor Signals and Is a Suppressor of Host Defense against Systemic Fungal Infection. Infect Immun. 2020 08 19; 88(9).  View on PubMed
  17. Poh AR, Dwyer AR, Eissmann MF, Chand AL, Baloyan D, Boon L, Murrey MW, Whitehead L, O'Brien M, Lowell CA, Putoczki TL, Pixley FJ, O'Donoghue RJJ, Ernst M. Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice. Cancer Immunol Res. 2020 04; 8(4):428-435.  View on PubMed
  18. Mahiddine K, Blaisdell A, Ma S, Créquer-Grandhomme A, Lowell CA, Erlebacher A. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J Clin Invest. 2020 01 02; 130(1):389-403.  View on PubMed
  19. Rohwedder I, Kurz ARM, Pruenster M, Immler R, Pick R, Eggersmann T, Klapproth S, Johnson JL, Alsina SM, Lowell CA, Mócsai A, Catz SD, Sperandio M. Src family kinase-mediated vesicle trafficking is critical for neutrophil basement membrane penetration. Haematologica. 2020 07; 105(7):1845-1856.  View on PubMed
  20. Cappenberg A, Margraf A, Thomas K, Bardel B, McCreedy DA, Van Marck V, Mellmann A, Lowell CA, Zarbock A. L-selectin shedding affects bacterial clearance in the lung: a new regulatory pathway for integrin outside-in signaling. Blood. 2019 10 24; 134(17):1445-1457.  View on PubMed

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