| Project/Area Number |
17310128
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Living organism molecular science
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
FUKASE Koichi Osaka University, GARDUATE SCHOOL OF SCJENCE, DEPARTMENT OF CHEMISTRY, PROFESSOR (80192722)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
FUJIMOTO Yukari OSAKA UNIVERSITY, GARDUATE SCHOOL OF SCIENCE, DEPARTMENT OF CHEMISTRY, ASSOCIATE PROFESSOR (00362616)
TANAKA Katsunori OSAKA UNIVERSITY, GARDUATE SCHOOL OF SCIENCE, DEPARTMENT OF CHEMISTRY, ASSISTANT PROFESSOR (00403098)
|
|---|
| Project Period (FY) |
2005 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥16,980,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2007: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2005: ¥6,600,000 (Direct Cost: ¥6,600,000)
|
|---|
| Keywords | INNATE IMMUNITY / IMMUNOSTIMULATION / GLYCOCONJUGATE / LIPOPOLYSACCHARIDE / PEPTIDOGLYCAN / RECEPTOR |
|---|
| Research Abstract |
Innate immunity is a phylogenetically ancient defense mechanism against pathogens such as bacteria and viruses. Lipopolysaccharide (LPS) of Gram-negative bacteria shows very strong immunostimulating activity and the active entity of LPS is lipid A. In order to investigate the structural basis for expression of the immunostimulating activity, we have synthesized various lipid A and the analogues such as carboxymethyl analogues at 1 position, acidic amino acid containing monosaccharides, conformationally-restricted analogues, and so on. Ru. gelatinosus lipid A having 6 acyl groups with symmetrical acylation distribution and 1- and 4'-phosphate groups showed potent antagonistic activity whereas its 1-O-carboxymethyl analogue showed cytokine inducing activity. The difference of theses two compounds is only 1-O-acidic functional groups. Similar biological results were obtained from the studies of monosaccharide analogues having acidic amino acids. The aspartic acid analogue having two carbo
… More
xyl groups showed weak but definite immunostimulating activity whereas phosphorerine analogue having one phosphate and one carboxyl group showed antagonistic activity. In both cases the small difference in anionic charge controls the biological activities and this is the new finding by the present study. Helicobacter pylori is a Gram-negative bacteria considered to be an etiological agent of gastroduodental diseases such as the chronic gastritis, gastroduodental ulcer and gastric cancer. H pylori LPS shows very low endotoxic activity and has the characteristic lipid Apart; (1) the presence of less number but of longer fatty acid residues; (2) the absence of the 4'-phosphate group; and (3) the presence of an ethanolamine group linked to the glycosyl phosphate functionality. We previously indicated that H pylori lipid A, which has tri-acyl groups and ethanolamine at the anomeric phosphate, shows weak immunostimulating activity。 In the present study, we synthesized the H pylori LPS partial structures, Kdo-lipid A and the lipid A having no ethanolamine at the anomeric phosphate and found that the compounds are antagonist.
Peptidoglycan partial structures have been synthesized in order to investigate the biofunctional mechanism including the interaction with peptidoglycan receptors, Nod1 and Nod2, and peptidoglycan recognition proteins. We concluded that another peptidoglycan receptor candidate TLR2 does not recognize fundamental structure of peptidoglycan. Potent Nod1 agonists having N-fatty acyl groups (acylated-iE-DAP) have been developed. These Nod1 agonists were used for the investigation of the Nod1 function in living body and we revealed that Nod1 functions at the early stage of bacterial infection. Structures composed of disaccharide and tripeptide or tetrapeptide having diaminopimelic acid (DAP) residue were synthesized. Tracheal cytotoxin (TCT) consisting in disaccharide having anhydrosugar structure and DAP containing tetrapeptide has been also synthesized for the first time. New peptidoglycan partial structures in which two glycan chains is cross-linked with a peptide chain were synthesized. Biological studies of these peptidoglycan partial structures indicated that both Nod1 and Nod2 recognized peptidoglycan partial structures but not intact peptidoglycan. Less
|
