| Project/Area Number |
13671052
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KOYAMA Takatoshi Tokyo Medical and Dental University, Graduate School of Health Sciences, Associate Prof., 大学院・保健衛生学研究科, 助教授 (20234916)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Keiko Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering, Instructor, 生体材料工学研究科, 助手 (90147017)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | thrombomodulin / tissue factor / gene transfer / plasmin inhibitor / non-viral gene transfer / protein C / factor VII activating enzyme / tumor necrosis factor / トロンボモジュリン / 組織因子 / プラスミンインヒビター |
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| Research Abstract |
1) Expression of thrombomodulin (TM)
We have found that with the mutations at positions -133 and -33, the TM gene expression may be decreased, and the decreased TM expression could not efficiently inhibit the effects of thrombin. These mutations may cause hyper-coagulable states, and increase atheroscierogenesis, leading to thromboembolic disorders such' as coronary diseases.
Transferrin receptor-facilitated in vivo gene transfer to the inferior vena cava resulted in sufficient TM gene expression and subsequent maintenance of thromboresistance even after exposure to arterial pressure. Our results had implications for applying this technology to coronary bypass operations.
2) Expression of tissue factor (TF)
We eluted the adsorbed leukocytes from extracorporeal circuits used for 6 patients by washing with EDTA-HEPES buffer. The leukocytes, representing 5 to 10% of the circulating leukocytes, were collected. Most were neutrophils expressing CD 11 b antigens as high as those in circulation du
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ring cardiopulmonary bypass (CPB). Adsorbed monocytes expressed TF higher than those in circulation. These results indicated that extracorporeal circuits adsorb a large number of activated neutrophils and a small number of highly thrombogenic monocytes during their use. Furthermore, we found the involvement of two distinct mechanisms for the appearance of TF-bearing leukocytes responsible for promoting coagulation during and after CPB: the quick appearance being partly explained by the formation of leukocyte-platelet complex that occurs mainly in the pericardial cavity, and the slow appearance via transcriptional activation in monocytes. These results suggested that the reinfusion of the wound blood containing activated monocytes could produce a procoagulant state in the patient body. To reduce the likelihood of this harmful reaction, it might be of use to remove monocytes from the wound blood washed by a cell-saving device by using a leukocyte filter. Another study demonstrated that some protease inhibitors might act as stress and induced TF expression with direct phosphorylation of JNK and p38, followed by phosphorylation and activation of AP-1 in monocytic cells.
3) Abnormality of intracellular transport of proteins in cases of congenital protein deficiencies
We have carried out molecular analysis of American family members with congenital plasmin inhibitor (PI) deficiency, and detected a single thymine deletion at nucleotide position 332 in exon 5. This is the 5th case of PI deficiency in which the genetic abnormality was identified. We further found that the mutant PI was retained and underwent progressive degradation by proteasome within the cells, and was minimally excreted into the media. Less
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