| Project/Area Number |
09470147
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
SOHMA Hitoshi (1998) Sapporo Medical University, School of medicine, Department of Biochemistry, Assistant Professor, 医学部, 講師 (70226702)
秋野 豊明 (1997) 札幌医科大学, 学長 (80045377)
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| Co-Investigator(Kenkyū-buntansha) |
SANO Hitomi Sapporo Medical University, School of medicine, Department of Biochemistry, Inst, 医学部, 助手 (80295344)
KUROKI Yoshio Sapporo Medical University, School of medicine, Department of Biochemistry, Prof, 医学部, 教授 (70161784)
小笠原 由法 札幌医科大学, 医学部, 講師 (20224090)
相馬 仁 札幌医科大学, 医学部, 講師 (70226702)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 1998: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1997: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | alveolar type II cells / surfactant apoprotein / C-type animal lectin / phospholipid binding protein / glycolipid binding protein / annexin IV / LPS / CD14 / 肺サーファクタント / サーファクタント蛋白質 / 生体防御 / アネキシン / SP-A / SP-D / ホスファチジルイノシトール |
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| Research Abstract |
Pulmonary surfactant, a mixture of lipids and proteins, is synthesized by alveolar type II cells and secreted to alveolar space. Surfactant proteins A and D (SP-A and SP-D) have been shown to play roles in phospholipid homeostasis and host defense in lung. In the present study, we focused on the functional roles of SP-A and SP-D, and on the SP-A binding protein (annexin IV)
1. SP-A and SP-D are homologous proteins and belong to the C-type lectin family. Both proteins bind to phospoholipids and glycolipids : SP-A to diparmitoylphosphatidylcholine (DPPC) and GalCer, and SP-D to phosphtidylinositol (PI) and GluCer. SP-A also inhibits phospholipid secretion by alveolar type II cells and augments uptake of phospohlipids via SP-A receptors, whereas SP-D does not have these properties. Using chimeric proteins with SP-A and SP-D, it was revealed that Glu^<195> to C-terminus of SP-A is important for the functional properties of SP-A and that Glu^<321> to C-terminus and Cys^<261> to C-terminus of
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SP-D are required for PI binding and GluCer binding, respectively.
2. Annexin IV is a member of the annexin family that consists of a unique N-terminal and a C-terminal core region. The core region consists of four consensus 70 amino acid-repeats (domains 1-4), in which Ca^<2+> and phospholipid binding sites are located. Using truncation mutants of annexin IV, SP-A binding site was shown to locate in domain 3 of annexin IV.Moreover, the Ca^<2+>-binding site in domain 3 of annexin IV and Arg^<197> of SP-A were also shown to be important for Ca^<2+>-dependent binding by site-directed mutagenesis study.
3. SP-A has been shown to interact with the Gram-negative bacteria. As LPS is the main constituent of the bacterial membrane, we investigate possible interaction between SP-A and LPS.It was revealed that SP-A bound to both rough LPS and lipid A but not to smooth LPS.LPS-induced augmentation of expression of TNF-alpha was attenuated by SP-A.SP-A was also shown to interact with CD14, which is the smooth LPS receptor. Therefore, SP-A inhibited LPS-induced TNF-alpha expression by competing with LPS for CD14. Less
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