Background and Aims
The main aim of our research is to understand the molecular and cellular mechanisms mediating inflammatory diseases and to translate our findings into therapeutic concepts to treat these diseases. The current projects are:
The functions and signalling mechanisms of eicosanoids and their receptors
Both prostaglandin D2 (PGD2) and cysteinyl leukotrienes (LTs) have been detected in high concentrations at sites of allergic inflammation. Through its action on its receptor CRTH2, PGD2 elicits many pro-inflammatory responses in leukocytes. Pharmacological inhibition of CRTH2 represents a promising new treatment for allergic diseases. The leukotriene antagonists, most notably montelukast, have been approved for clinical use in asthma, and are effective inhibiting the CysLT1 (one of the receptors for LTs)-mediated bronchoconstriction but their anti-inflammatory activity is modest.
Our recent studies demonstrated that LTs, especially LTE4, greatly enhanced the inflammatory responses of human Th2 cells to PGD2. This synergistic effect was inhibited by montelukast. Combination of a CRTH2 antagonist and montelukast was required to completely inhibit the responses induced by the combination of PGD2 and LTs. The aim of the project is to understand comprehensively the functions and mechanism of these mediators in the pathogenesis of mast cell-mediated allergic inflammation and to provide the rationale for clinical use of antagonists targeting CRTH2 and leukotriene receptors, and finally lead to novel therapeutic strategy for the treatment of asthma.
The role of group 2 innate lymphoid cells (ILC2) in allergic asthma
Activation of ILC2 population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Increased numbers of ILC2 have been detected in the inflamed nasal polyps and skin. In animal models the development of airway eosinophilia and airway hyperresponsiveness has been shown to be dependent on ILC2. We have also demonstrated the important role of PGD2 and its receptor CRTH2 in bridging innate and adaptive pathways in ILC2 cells. In this project, we would like to investigate 1) the profile of ILC2 in different sub-group of asthmatic patients including eosinophilic and neutrophilic severe asthma; 2) the potential role of ILC2 the pathogenesis of these patients; 3) the biology of ILC2.
Mechanism of RORγt and drug development for IL-17 mediated inflammatory diseases
Nuclear hormone receptor RORγt plays important role in physiological and pathological processes. RORγt+Th17 cells represent 30% of infiltrating T cells in some inflammatory diseases such as psoriasis. Small molecule inhibitors of RORγt inhibit the differentiation of human Th17 cells in vitro and reduce Th17 cell numbers and disease activity in animal models. Comprehensive understanding of the role and mechanism of the activation of RORγt in RORγt positive cells will be a critical step prior to utilization of RORγt as a therapeutic approach for the treatment of ROR-mediated disorders. The aims of our project are:
- Investigating the role of RORγt in the function of RORγt+ cells during their differentiation and after that;
- Understanding the impact of RORγt inhibition on transcriptional regulation and function of RORγt+ cells;
- Drug screening for RORγt inhibitor and further development of these drug candidates into clinical trials in collaboration with a pharmaceutical company.