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
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
- 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
- Lowell CA. Hyperuricemia reduces neutrophil function. Blood. 2022 06 09; 139(23):3354-3356.
View on PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Go to UCSF Profiles, powered by CTSI