Clifford Lowell, MD, PhD

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

The Lowell laboratory studies tyrosine kinase and phosphatase 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, STIM2) 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 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 cytoplasmic tyrosine phosphatases (mainly SHP1) in the counter regulation tyrosine kinases, especially in the setting of hematopoietic malignancy and inflammatory disease. Recent publications highlight the role of SHP1, as a negative regulator of anti-tumor immunity, as well as the role of integrin signaling adapter protein SKAP2 in human autoimmune disease, in particular type 1 diabetes. Publications total = 228; h-index 97.

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

Websites

Publications: 

Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy.

Science advances

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

A dominant function of LynB kinase in preventing autoimmunity.

Science advances

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

Spleen tyrosine kinase facilitates neutrophil activation and worsens long-term neurologic deficits after spinal cord injury.

Journal of neuroinflammation

McCreedy DA, Abram CL, Hu Y, Min SW, Platt ME, Kirchhoff MA, Reid SK, Jalufka FL, Lowell CA