NOVEL CHAPERONE INDUCERS FOR LIVER TRANSPLANTATION

用于肝移植的新型伴侣诱导剂

基本信息

批准号：
12557105
负责人：
ROKUTAN Kazuhito
金额：
$ 3.26万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

In response to various environmental stresses, mammalian cells induce a set of proteins called heat shock proteins (HSP). Overproduction of HSP, particularly a stress-inducible 70-kDa protein (Hsp70), results in the acquisition of tolerance against various types of stresses. Over the last 10 years, various experiments have been performed to examine clinical applications of Hsp70, using heat-shocked animals and gene targeting animals. At the same time, several groups introduced chaperone inducers that safely and selectively induce Hsp70. An acyclic isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a non-toxic Hsp70 inducer, which selectively and safely induced Hsp70 in cultured guinea pig gastric mucosal cells and rat gastric mucosa, and suppressed ethanol-induced cell damage and stress ulcer formation, respectively. GGA can also prime other types of cells for enhanced induction of Hsp70, when exposed to subsequent stress. Pretreatment of rats with this compo … More und markedly rendered ischemia-reperfusion injury of the rat liver, small intestine, or heart, and improved survival after 95% hepatectomy as well as liver transplantation. In this study, we screened 12 derivatives of acyclic polyisoprenoid using primary cultured guinea pig gastric mucosal cells and rat hepotocytes and found that geranylgeraniol (GGO) was the most effective inducer for Hsp70 and exerted the most potent cytoprotective actions on these cells. The Hsp70-inducing action of GGO was confirmed by ischemia-reperfusion injury of rat livers. However, we failed to detect any beneficial effects on a rat liver transplantation model. GGA can block insult-induced apoptotic pathways at multiple steps ; it inhibited activation of c-Jun N-terminal kinases, decline of mitochondrial membrane potential, and formation of apoptosome by binding with Apafl. Recently, GGA has been shown to induce thioredoxin and anti-viral genes, suggesting that GGA may exhibit cytoprotective actions independently of Hsp70 induction. In addition to the Hsp70 inducer, such as GGA or GGO, new compounds targeting ER chaperones may be useful for the treatment of folding diseases. Less

为了应对各种环境应激，哺乳动物细胞诱导一系列称为热休克蛋白 (HSP) 的蛋白质，HSP 的过量产生，特别是应激诱导的 70-kDa 蛋白 (Hsp70)，导致获得对各种类型应激的耐受性。在过去的 10 年里，人们利用热休克动物和基因靶向动物进行了各种实验来检验 Hsp70 的临床应用，同时，多个研究小组引入了安全、选择性诱导的伴侣诱导剂。 Hsp70。首次引入一种无环类异戊二烯香叶基香叶基丙酮（GGA）作为无毒的 Hsp70 诱导剂，在培养的豚鼠胃粘膜细胞和大鼠胃粘膜中选择性、安全地诱导 Hsp70，并抑制乙醇诱导的细胞损伤。当暴露于后续的应激时，GGA 还可以分别促进其他类型的细胞增强 Hsp70 的诱导。使用该组合物的大鼠显着引起大鼠肝脏、小肠或心脏的缺血再灌注损伤，并提高了 95% 肝切除术和肝移植后的存活率。在这项研究中，我们使用无环聚异戊二烯筛选了 12 种无环聚异戊二烯衍生物。原代培养豚鼠胃粘膜细胞和大鼠肝细胞，发现香叶基香叶醇（GGO）是Hsp70和Hsp70最有效的诱导剂。 GGO 对这些细胞发挥了最有效的细胞保护作用，通过大鼠肝脏的缺血再灌注损伤证实了 GGA 的 Hsp70 诱导作用，但我们未能检测到 GGA 可以阻止损伤诱导的任何有益作用。多步骤凋亡途径；最近，GGA 已被证明可以通过与 Apafl 结合来抑制 c-Jun N 末端激酶的激活、线粒体膜电位的下降和凋亡体的形成。诱导硫氧还蛋白和抗病毒基因，表明 GGA 可能表现出独立于 Hsp70 诱导的细胞保护作用。