Development of a new drug for heart failure

开发治疗心力衰竭的新药

基本信息

批准号：
14370032
负责人：
INUI Makoto
金额：
$ 8.7万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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 systemWe reconstituted the molecular interaction between SERCA and phospholamban using fusion proteins of cytoplasmic regions of each protein. Optimizing the conditions for … More a 384-well plate, we succeeded in development of a screen method for a drag which targets the SERCA-phospholamban system2.Searching for factors which modulate oligomeric structure of phospholambanSince 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

心脏肌肉的收缩和钙离子（CA）在这些过程中扮演蛋白质磷酸的角色，我们研究了SERCA和国际因素之间的分子相互作用。 Serca-Phospholamban System2。搜索仅磷脂的模块化结构，而不是单体形式，而不是五聚体形式，即Spholambimbits Serca，重要的是要鉴定一些动态均衡的态度。解离的人可以影响心脏肌肉的收缩性，五型磷酸化的磷酸化和磷酸化活性磷龙的五聚体形式可能会改善心肌功能