Siminovitch Lab


My group's research programme is focused on identifying the genetic and cellular mechanisms modulating expression of the immune response and development of immunologic diseases. To this end, we have focussed our efforts on identifying the genes responsible for several immune diseases, the human X-linked immunodeficiency disease, Wiskott-Aldrich syndrome, and a murine model of systemic autoimmune and chronic disease known as the motheaten syndrome. With regards to Wiskott-Aldrich syndrome (WAS), until recently our efforts have been largely targeted toward isolation of the disease gene using a positional cloning approach. However, the gene has just been identified and studies aimed at delineating the function of the gene product and in particular its role in lymphocyte function are now underway in our lab. With respect to the motheaten syndrome, we have previously shown that this distinct phenotype is caused by loss-of-function mutations in the gene encoding a cytoplasmic tyrosine phosphatase, SHP-1. Thus, our research efforts in relation to the motheaten syndrome are now targeted toward elucidating the biological functions of SHP-1 and the molecular events linking SHP-1 mutation to expression of severe systemic autoimmunity and inflammation.

Another thrust of our group's research involves the use of a positional cloning approach to identify genes conferring susceptibility to chronic inflammatory diseases, and in particular asthma and the inflammatory bowel diseases (IBD), Crohn's and ulcerative colitis. With respect to the work on IBD, we (our group in collaboration with Drs. Zane Cohen, Gord Greenberg, Robin McLeod and Hillary Steinhart) have identified a number of families in which multiple individuals are affected by Crohn's or ulcerative colitis and are now beginning to analyse these families by genetic linkage analysis so as to map IBD-related genes and thereby lay the groundwork for the cloning and characterization of these genes.


Patients with Wiskott-Aldrich syndrome (WAS) manifest severely impaired humoral and cellular immunity and also markedly reduced platelet number and function. While the sequence of the WAS gene product (WASP) reveals this protein to be distinct from all other known proteins, our preliminary data suggest that WASP represents a signaling effector which links lymphocyte stimulation to cytoskeletal reorganization. Our future work on WAS will therefore continue to focus on delineating WASP function in normal lymphocytes and platelets and defining the molecular mechanisms linking WASP mutation to the phenotype expressed by WAS patients.

Along similar lines, our future work on the motheaten mouse is targeted toward clarifying how PTP1C mutation causes the marked haemopoietic dysregulation and systemic autoimmunity and inflammation manifested by these animals. As PTP1C deficient motheaten mice develop an enormous overexpansion of monocyte, myeloid and early erythroid cells, it appears likely that PTP1C is involved in downregulating signaling pathways which normally evoke proliferation of these cells. The postulate of a role for PTP1C in suppressing cell proliferation is supported by our recent results showing the capacity of PTP1C to suppress antigen-receptor driven proliferation of both B and T lymphocytes. In addition, our finding that motheaten heterozygous mice who are normal in early life, develop adenocarcinomas and lymphomas over time suggests that PTP1C acts as a tumor suppressor in some cell lineages. Overall, these data indicate that PTP1C plays an important role in regulation of haematopoietic/immune cell function and our future work will therefore involve the use of PTP1C deficient motheaten mice as well as mice deficient for both PTP1C and other key haemopoietic signaling effectors (such as CD45, Fas and CD40 lig) to delineate the mechanisms whereby PTP1C activity impacts on autoimmunity, inflammation, malignant transformation and other pathologic states.