Potential Rotation Projects

1. SOX proteins in the maintenance of mucosal tissue integrity and innate immunity. There are ~20 Sox genes in mammals. Although the prototypic SOX-related proteins, SRY (Sex-determining gene on Y chromosome) and TCF/LEF are reasonably well characterized, very little is known about the relevance of SOX proteins in lymphocyte development and function. We have discovered that some SOX proteins can regulate the WNT/Wingless signaling cascade, a central morphogenetic pathways specifying cell fate in all organisms whose aberrant activity leads to tumourigenesis. Importantly, expression of specific combinations of Sox genes is lymphocyte subset-specific, temporally and spatially. Our results so far strongly indicate that Sox genes are important regulators of multiple lymphocyte subsets, in part by opposing WNT signaling. An impediment to advances in understanding Sox gene functions has been that they are critical for embryonic development and mutations lead to early lethality. We have therefore embarked on generating conditional KO mice of various Sox genes and their cofactors that we postulate are centrally involved in lymphocyte differentiation and function. A few rotation projects are available to analyze these newly derived mouse models, both at the level of cellular and molecular analysis of lymphocyte development and single-cell tracking of specific Sox gene expressing cells in vivo. These mice have defects in mucosal tissue barrier functions and often exhibit aberrant inflammatory responses in the skin that can model human skin diseases such as psoriasis and dermatitis.

a. analysis of Sox13 reporter mice

b. analysis of Sox4-deficient mice for innate lymphocyte developmental defects

c. analysis of spontaneous skin inflammation in mice lacking dermal innate IL-17 producers

d. analysis of global chromatin docking of HMG TFs in ex vivo T cells

e. comparative analysis of global gene regulation and gene networks across all hematopoietic cells

2. Testing small molecule compounds to treat organ-specific T cell-mediated autoimmunity in mice (e.g. Type I Diabetes, colitis and the mouse model of multiple sclerosis).

3. Analysis of mice with novel mutations in TGFb signaling to investigate the role of TGFb in regulating self-destructive T cells.