Clifford Lowell, MD, PhD

Distinguished Professor & Chair
Department of Laboratory Medicine
+1 415 476-2963
Research Description: 

The Lowell 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 (such as Fc?Rs) 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. Publications total = 191

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Regulation of Intracellular Signaling in Innate Immune Cells

Websites

Publications: 

Complement activation on endothelium initiates antibody-mediated acute lung injury.

The Journal of clinical investigation

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

ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense.

Proceedings of the National Academy of Sciences of the United States of America

Grimes D, Johnson R, Pashos M, Cummings C, Kang C, Sampedro GR, Tycksen E, McBride HJ, Sah R, Lowell CA, Clemens RA

The ubiquitin-modifying enzyme A20 terminates C-type lectin receptor signals and is a suppressor of host defense against systemic fungal infection.

Infection and immunity

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

Inhibition of the SRC kinase HCK impairs STAT3-dependent gastric tumor growth in mice.

Cancer immunology research

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 RJ, Ernst M

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils.

The Journal of clinical investigation

Mahiddine K, Blaisdell A, Ma S, Créquer-Grandhomme A, Lowell CA, Erlebacher A