Research
The immune system consists of two evolutionarily different but closely related arms, innate immunity and adaptive immunity. The harmonized interaction of these two immune responses is required for efficient combat against hazardous pathogens and cancers. Our laboratory focuses on the mechanism of the innate immune system, its connection to the adaptive immune response, and disease pathogenesis caused by dysregulation of innate immune response.

Signaling of Toll-like receptors
A variety of microbial products are detected by a family of germline-encoded cell surface receptors called Toll-like receptors (TLRs). TLRs are evolutionarily conserved proteins that recognize specific pathogens or pathogen associated molecular patterns (PAMPs) and trigger signaling cascades leading to host immune responses and inflammation. One of our goals is to reveal the molecular mechanism of signaling and regulation of the Toll-like receptor system. To achieve this goal, we are using mutant mice which either lack or overexpress genes involved in TLR signaling.

NBD-LRR proteins
Another gene family casts a new light on innate immune recognition. This cytoplasmic protein family, termed collectively NBD-LRR or Nod, is characterized by two motifs: nucleotide binding domain (NBD) and leucine rich repeats (LRR). Genomic sequence analysis revealed that NBD-LRR is a very diverse protein family. As this family shows similarity to the NBD-LRR type of disease-resistance genes in plants, it is likely that humans have NBD-LRR protein to detect broad various pathogens. Our effort is focusing on the function of this protein family, especially on mechanisms of pathogen detection and signaling cascades and their significance against infectious diseases.

Activation of adaptive immunity by innate immunity
Activation of innate immunity, either via TLRs or NBD-LRR proteins, is a first line of defense against pathogens or cancerous cells and leads to the activation/regulation of lymphocytes, i.e., the adaptive immune system. We aim to find the mechanism of how these two systems interact with each other by using cells/animals which lacks signaling molecules for TLRs, NBD-LRRs or NBD-LRR per se.

Pathogenesis of inflammatory disease
Several lines of evidence suggest that poorly regulated activation of innate immune system could result in chronic inflammatory diseases; Mutations of the Nod2 gene, one of NBD-LRR, are frequently observed in Crohn’s disease patients and TLR signaling is essential for lupus pathogenesis in certain strain of mice. We aim to reveal such disease pathogenesis using mouse models; by which dysregulated innate immune response cause inflammatory diseases.

(Above) Model of signaling in the innate immune system
Pathogens are detected by TLRs which activate a signaling cascade consisting of MyD88, IRAK and TRAF6 (1). IRAK-M inhibits this signaling via negative feedback and regulates homeostasis of the TLR system (2). Nod family proteins detect products from pathogens such as MDP in the cytoplasm directly or indirectly (3). Nod proteins activate downstream molecules such as RIP2 leading to protection from pathogens (4).
(1) Medzhitov R. et.,al. 1997 Cell
(2) Kobayashi K. et.,al. 2002 Cell
(3) Kobayashi K. et.,al. 2005 Science
(4) Kobayashi K. et.,al. 2002 Nature