2004 Fiscal Year Final Research Report Summary
Development of a new drug for heart failure
| Project/Area Number |
14370032
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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 |
General pharmacology
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| Research Institution | Yamaguchi University |
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Principal Investigator |
INUI Makoto Yamaguchi University, School of Medicine, Professor, 医学部, 教授 (70223237)
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| Co-Investigator(Kenkyū-buntansha) |
KIMURA Yoshihiro Yamaguchi University, School of Medicine, Associate Professor, 医学部, 助教授 (90301308)
YAMADA Yasue Yamaguchi University, School of Medicine, Assistant Professor, 医学部, 講師 (00166737)
KO Ji-ae Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (70314797)
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| Project Period (FY) |
2002 – 2004
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| Keywords | A drug for heart failure / SERCA / Phospholamban / Cardiac sarcoplasmi reticulum / Intracellular Ca^<2+> transport / Protein-protein interaction / Screening |
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| Research Abstract |
Contraction and relaxation of heart muscle is regulated by intracellular calcium ions (Ca). Especially, Ca pumps (SERCA) and Ca release channels of cardiac sarcoplasmic reticulum (SR) play pivotal roles in these processes. SERCA of heart muscle is modulated by another SR protein phospholamban which inhibits the activity of SERCA. Removal of the inhibition by phospholamban facilitates relaxation of heart muscle and increases the contractility. It has been shown that removal of phospholamban inhibition improves heart failure. In order to develop a new drug for heart failure, we investigated the molecular interaction between SERCA and phospholamban and factors that modulate the interaction. The followings are the summary of our results.
1.Development of a screening method for a drug which targets the SERCA-phospholamban system
We reconstituted the molecular interaction between SERCA and phospholamban using fusion proteins of cytoplasmic regions of each protein. Optimizing the conditions for
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a 384-well plate, we succeeded in development of a screen method for a drag which targets the SERCA-phospholamban system
2.Searching for factors which modulate oligomeric structure of phospholamban
Since only the monomeric form, not a pentameric form, of phospholamban inhibits SERCA, it is important to gain insight into the dynamic equilibrium between these two forms. Factors that increase the monomeric form dissociating the oligomer can potentially affect the contractility of heart muscle. Among the eight phospholipids examined, phosphatidic acid was an effective inducer of pentamer dissociation, whereas the other phospholipids exhibited pentamer-stabilizing activity. Lysophosphatidylcholine, lysophosphatidylethanolamine, and phosphatidylglycerol were highly effective stabilizers of the pentamer. The phospholipids in the SR membrane are thus important determinants of the equilibrium between the monomeric and pentameric forms of this protein. Our results suggest that a drug that directly or indirectry through phospholipase D increases the pentameric form of phospholamban potentially improves heart muscle function. Less
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Research Products
(13 results)
