About

Dr. Gerald Krystal, Ph.D
Senior Scientist

• Terry Fox Cancer Research Scientist of the NCI
• Professor, Pathology & Laboratory Medicine, University of British Columbia (UBC)
• Member, Experimental Medicine, University of British Columbia (UBC)
• Member, Genetics, University of British Columbia (UBC)

Research Interest

• THE ROLE OF SHIP IN HEMOPOIESIS AND INNATE IMMUNITY

Studies in Dr. Krystal's laboratory have focused on the hemopoietic-restricted negative regulator of the phosphatidylinositol-3 kinase (PI3K) pathway, SHIP (SH2-containing inositol 5'-phosphatase). This important negative regulator of hemopoietic cell proliferation, survival, and end cell activation appears to carry out its inhibitory function, at least in part, by translocating to the plasma membrane and hydrolysing the critical PI3K-generated second messenger, PI-3,4,5-P3, to PI-3,4-P2. Consistent with this, SHIP-/- mice suffer from a progressive myeloproliferative disorder because their myeloid progenitors display an enhanced survival/proliferation under limiting growth factor conditions. In addition to a dramatically increased number of neutrophils and monocyte/macrophages, SHIP-/- mice are also severely osteoporotic (have thin, fragile bones) because of an overabundance of osteoclasts. Comparing mast cells from SHIP+/+ and -/- mice, his lab has found that SHIP acts as a "gatekeeper" of mast cell activation, preventing degranulation by IgE alone, restraining IgE+antigen-induced degranulation and limiting the production of inflammatory cytokines and arachidonic acid metabolites from these cells. It also reduces IgE-induced adhesion of mast cells to fibronectin. Interestingly, SHIP also appears to play a role in restraining the differentiation of hemopoietic progenitors since both Lin- Sca1+ bone marrow cells or embryonic stem (ES) cells from SHIP-/- mice differentiate into mature mast cells and macrophages significantly faster than their wild type counterparts. Also of interest, his lab has recently found SHIP is dramatically upregulated following microbial activation of macrophages in mice. This increase in SHIP makes the mice more susceptible to microbial infections but, at the same time, less susceptible to septic shock (which occurs when we overreact to an infection). His lab has also found that an elevated PI3K pathway skews the development of macrophages towards M2 healers (and away from tumour destroying M1 killer macrophages) and that SHIP prevents this skewing. This could be very important for the treatment of cancer since growing tumours are typically heavily infiltrated with macrophages and yet the tumour cells continue to thrive because they secrete factors that skew macrophage development towards an M2 phenotype. This subversion allows the tumour cells to grow by avoiding the production of toxic NO from M1 macrophages and utilizing the growth promoting properties of these M2 cells. His lab has recently developed an in vitro macrophage differentiation assay system that mimics in vivo differentiation in order to identify factors that can skew differentiation either towards M1 or M2 macrophages for future therapeutic treatments of cancer and inflammatory disorders.

Publications

Lab People

Open Positions

None Available at this time.