My research focuses on the molecular mechanisms of human autoinflammatory diseases. Autoinflammation is usually caused by dysregulation of innate immune system, particularly that of proinflammatory cytokine production. I am studying a group of autoinflammatory diseases that is caused by dysregulation of IL-1beta. IL-1beta family of proinflammatory cytokines are atypical cytokines that are synthesized as inactive precursors in the cytoplasm. Maturation and secretion of these cytokines depends on inflammasomes, large protein complexes formed in response to pathogenic infection or tissue damage. Mutations in genes encoding inflamamsome components that lead to constitutive activation of inflammasome acitivation result in autoinflammatory conditions such as Cryopyrinopathies. Studies of these diseases have greatly advanced our knowledge of inflammasome activation and have lead to the successful treatment of common inflammatory diseases such as gout arthritis with anti-IL-1 therapeutics.
Pyogenic Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome is another form of autoinflammatory disease that manifests with sterile inflammatory arthritis and skin lesions that is potentially caused by over-production of IL-1 beta. Using conditional gene targeting, I have established a mouse model of human PAPA syndrome, which partially recapitulates symptoms discovered in human patients such as elevated production of proinflammatory cytokines.
Mevalonate pathway is the fundamental metabolic pathway for cholesterol synthesis. Recent clinical studies have shown that mutations in the gene encoding the rate-limiting enzyme mevalonate kinase cause autoinflammatory conditions termed mevalonate kinase deficiency (MKD). It is interesting that the inflammatory symptoms found in MKD patients can be treated with anti-IL-1 therapeutics, suggesting that IL-1 plays a pivotal role in the pathogenesis. How cholesterol synthesis pathway intervene with IL-1 processing and secretion remains enigmatic. My preliminary study indicated that products in the mevalonate pathway may be involved in the regulations of the assembly of inflammasomes. Using conditional gene targeting in combination with biochemical, genomic and proteomic tools, we are dissecting the multiple layer of this enigma.
