PAPD5小分子抑制剂可用于恢复病人干细胞的端粒酶

产品分类

联系我们

美高梅导航赌城

当前位置:主页 > 美高梅导航赌城 >

PAPD5小分子抑制剂可用于恢复病人干细胞的端粒酶

2020-04-23 19:27

本期文章:《细胞—干细胞》:Online/在线发表

哈佛干细胞研究所Suneet Agarwal研究组的一项工作开发出了一种PAPD5小分子抑制剂,可用于恢复病人干细胞的端粒酶活性。该研究于2020年4月21日在线发表在《细胞—干细胞》上。

研究人员报道了PAPD5的小分子抑制剂,该抑制剂在体外、干细胞模型和体内能够恢复端粒活性。PAPD5是一种非经典聚合酶,可寡聚腺苷酸化并使端粒酶RNA组分(TERC)不稳定。

 

研究人员鉴定到了BCH001,这是一种特异的PAPD5抑制剂,可在先天性角化病(DC)患者诱导的多能干细胞中恢复端粒酶活性和端粒长度。当将经过工程改造的人血干细胞(携带了能够导致DC的PARN突变)移植到免疫缺陷小鼠中时,使用改造的PAPD5抑制剂(dihydroquinolizinone RG7834)进行口服治疗,可以挽救TERC 3'末端成熟和端粒长度。

 

这些发现为开发系统性端粒疗法铺平了道路,从而能够治疗DC、肺纤维化和其他可能与衰老相关疾病中的干细胞衰竭。

 

据介绍,降低端粒酶活性的遗传损伤会抑制干细胞复制,并导致一系列不治之症,包括先天性角化病(DC)和肺纤维化。恢复全身干细胞端粒酶的方式尚不清楚。

 

附:英文原文

Title: Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

Author: Neha Nagpal, Jianing Wang, Jing Zeng, Emily Lo, Diane H. Moon, Kevin Luk, Roman O. Braun, Lauri M. Burroughs, Sioban B. Keel, Christopher Reilly, R. Coleman Lindsley, Scot A. Wolfe, Albert K. Tai, Patrick Cahan, Daniel E. Bauer, Yick W. Fong, Suneet Agarwal

Issue&Volume: 2020-04-21

Abstract: Genetic lesions that reduce telomerase activity inhibit stem cell replication andcause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonaryfibrosis (PF). Modalities to restore telomerase in stem cells throughout the bodyremain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstratetelomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomeraseRNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restoredtelomerase activity and telomere length in DC patient induced pluripotent stem cells.When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with arepurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3′ end maturationand telomere length. These findings pave the way for developing systemic telomeretherapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-relateddiseases.

DOI: 10.1016/j.stem.2020.03.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30138-7

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx

地址:广东省广州市天河区88号 版权所有:Copyright © 2002-2019 美高梅平台娱乐 版权所有

技术支持:织梦58

扫一扫,加关注