| Co-Investigator(Kenkyū-buntansha) |
DOI Takefumi Osaka University Dept. Pharmaceutical Sciences Associate Professor., 薬学部, 助教授 (00211409)
NAGANO Hiroyuki Chugai Pharmaceutical Scientist., 研究所, 主席研究員
SADAHIRO Ryuhzou Chugai Pharmaceutical Director., 研究開発企画部, 部長
NAGANO Yutaka Kyoto University, Dept. Geriatric Medicine Scientist., 医学部老年科, 助手 (80228048)
KITA Tohru Kyoto University, Dept. Geriatric Medicine Professor., 医学部老年科, 教授 (60161460)
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| Research Abstract |
In order to develop the novel method to prevent and treat atherosclerotic disorders, we have studied the molecular mechanism by which plasma cholesterol accumulates in the artery wall. This project was focused on three major targets, 1) How cholesterol accumulates in macrophages through scavenger receptor mediated endocytosis? 2) The modification of LDL and the recognition of modified LDL by scavenger receptors, 3) Analysis of anti-oxidants which specifically prevent the modification of LDL. The results of these studies provide the novel informations for the treatment of atherosclerotic disorders.
(1) Molecular biology of macrophage scavenger receptors: We have cloned human, bovine, murine, and rabbit scavenger receptors cDNA and human and murine genomic DNA clones. The functional protein domains were studied using the protein engineering methods, and the molecular model of ligand-scavenger receptor interaction was proposed. The organization, chromosomal localization and polymorphism of human gene was studied.
(2) The interaction of modified LDL (acetyl-LDL and oxidized LDL) and scavenger receptor ligand binding domain was studied. The oxidation of LDL, which leads to the uptake by scavenger receptors, can be initiated by the various methods including the usage of metal ion (CuSO4), chemical reagent (AAPH,AMVN) or enzymes (15-lipoxygenase). The critical step of this reaction was the generation of cholesterol ester radical.
(3) In order to prevent the development of atherosclerosis, the inhibitor for LDL modification should be 1)accumulated in the core region of LDL, 2)able to prevent the generation of cholesterol ester radical, and 3)able to enhance the reverse cholesterol transport from macrophages.
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