Elucidation of the Molecular Mechanism of Atherosclerosis Induced by Unsaturted Lysophosphatidic Acid and Establishment of the Anti-athrosclerotic Therapy
| Project/Area Number |
15390246
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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 |
Circulatory organs internal medicine
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| Research Institution | Osaka University |
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Principal Investigator |
SHIBATA Katsushi Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70296565)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Ken-ichiro Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90238105)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2004: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥11,300,000 (Direct Cost: ¥11,300,000)
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| Keywords | Vascular Smooth Muscle Cells / Unsaturated LPA / Atherosclerosis / SHP-2 / Novel Unsaturated-LPA Receptor / Atherosclerotic Mouse / epiregulin |
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| Research Abstract |
The molecular mechanism of atherosclerosis still remains to be elucidated. The purposes of this study are to clarify the pathological significance of unsaturated-LPA in atherosclerosis and to develop the novel therapeutic strategy for atherosclerosis. Following experiments were performed. 1,Cloning of the novel unsaturated-LPA specific receptor : We are in the final step in the following experiments ; (1)Expression cloning using unsaturated-LPA stimulated activation of the ERK and p38MAPK as a functional marker, (2)The receptor binding experiment using radiolabeled unsaturated-LPA as a ligand. 2,Identification of the atherogenic factors : Using primary culture system of vascular smooth muscle cells(VSMCs) maintaining a differentiated phenotype, we demonstrated that epiregulin was released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for the progression of atherosclerosis (Circulation. 2003 18;108:2524-9.). 3,In vivo effect of unsaturated-LPA o
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n the atherogenesis. We demonstrated that treatment of rat common carotid arteries(CCAs) with 18:1 but not 18:0 LPA potently induced neointimal formation and that the coordinated activation of the ERK and p38MAPK pathways in the CCAs was critical for the 18:1 LPA-induced vascular remodeling in vivo (Circulation.2003 108:1746-52.). 3,Elucidation of the intracellular signal transduction involved in the pathogenesis of atherosclerosis : We demonstrated that IGF-I activated a protein-tyrosine phosphatase, SHP-2 in differentiated VSMCs and that the activated SHP-2 then dephosphorylated insulin receptor substrate-1(IRS-1), resulting in blockade of the activation of the ERK and p38MAPK pathways which are critically involved in de-differentiation of VSMCs. The results indicate that the IRS-1/SHP-2 interaction acts as a switch controlling phenotypic modulation of VSMCs (J.Biol.Chem.2004 279:40807-40818.). 4,Generation of atherosclerotic mouse : We have generated the transgenic mouse over-expressing the enzyme involved in the lipid synthesis, which is expected to have a disorder in the lipid metabolism. Less
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Report
(3 results)
Research Products
(10 results)
