Introduction


Specific aims：

(1) Elucidation of action mechanisms of lipid mediators, including sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), and development of drugs related to their actions.

(2)Elucidation of the physiological and pathophysiological roles of proton-sensing GPCRs, especially focusing on central nervous system, bone remodeling, and inflammatory disorders.




On-going projects






On-going projects


1. Role of lysolipid mediators and development of drugs targeted for their receptors

Lysolipid mediators, such as sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), have been shown to regulate a variety of biological processes, including proliferation, migration, and apoptosis, through G-protein-coupled receptors. Five S1P receptors, S1P1~5, and six LPA receptors, LPA1~6 have been reported. Since LPA exerts a variety of responses in cellular systems, the receptor agonists and antagonists may be therapeutically useful drugs. We have currently developed an LPA antagonist Ki16425 and its orally active Ki16198, in collaboration with Kirin brewery Co. Ltd. This drug is potentially applicable for cancer cell invasion and metastasis, cardiovascular diseases and inflammatory diseases.

(1) Role of S1P binding protein, apolipoprotein, on S1P release.

(2) Analysis of the inhibitor of autotaxin, an enzyme for LPA synthesis, on tumorigenesis.



2. Physiological and pathophysiological roles of proton-sensing GPCRs

We have recently found that a group of GPCRs sense extracellular pH and are coupled to the intracellular signaling pathways. As proton-sensing mechanisms, channels, such as TRPV1 (pH 4~6) and ASICs (pH 4~7), on sensory neurons have been known as a sensor for nociception and taste. Glutamic acid and aspartic acid (pKa 4.7) is shown to sense extracellular protons in these channels. On the other hand, OGR1 family GPCRs sense more physiological pH of 6~8 through histidine residues. They are expressed on a variety of cell types, including neural cells. Extracellular protons are 40 nM (pH 7.4) under the physiological and reach 1000 nM (pH 6.0) in tumor, ischemia, and inflammation. We are investigating the physiological and pathophysiological role of proton-sensing GPCRs using knockdown cells with siRNAs and knockout mice.



(1) Role of proton-sensing GPCRs in microglia and neuronal cells.

(2) Role of proton-sensing GPCRs in bone remodeling and tumorigenesis.

(3) Analysis of the role of proton-sensing GPCRs using asthma model, brain ischemia model, and arthritis model.

(4) Characterization of novel proton-sensing GPCR antagonists.