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Nat Metab :破解1型糖尿病治疗难题,哈佛科学家找到保护胰岛β细胞的新方法

2020-07-29 学术经纬 学术经纬

近年来,通过干细胞培育大量能够制造胰岛素的β细胞,有望为糖尿病患者带来细胞替代疗法。对于1型糖尿病,人体免疫系统会攻击自身的胰岛β细胞,在没有免疫抑制的情况下,复发性自身免疫也会迅速破坏移植的β细胞。

近年来,通过干细胞培育大量能够制造胰岛素的β细胞,科学家们有望为糖尿病患者带来细胞替代疗法。不过,这条路上横亘着一道障碍:如何保护这些β细胞免于遭受免疫系统的攻击。对于1型糖尿病来说,人体免疫系统会攻击自身的胰岛β细胞,在没有免疫抑制的情况下,复发性自身免疫也会迅速破坏移植的β细胞。

知名糖尿病研究机构、哈佛医学院乔斯林糖尿病中心(Joslin Diabetes Center)的科学家们在《自然》子刊Nature Metabolism上报告了一项研究发现,为逾越上述难关指出一条不寻常的新途径!他们找到的靶点,有望为移植的β细胞撑起一把“保护伞”。更可喜的是,实验表明,一种现有的药物可以作用于这一靶点,在1型糖尿病小鼠模型上起到移转症状的效果。

在本项研究中,科学家们首先采用基于CRISPR的技术,在模拟1型糖尿病的小鼠模型中,对β细胞系进行了全基因组筛选,以便找出某种可能保护β细胞的基因突变。

功夫不负有心人,在筛选出来的十多个基因中,他们注意到一个很有希望的靶标,即编码renalase蛋白的基因Rnls。此前,有研究表明,在人类基因组中,这一基因可能与1型糖尿病有关。

利用CRISPR进行全基因组筛选,找到保护β细胞的基因突变。

接下来,在小鼠的一部分胰岛β细胞中,科学家们功能性“敲除”了这一基因,在另一些β细胞中则予以保留。随后,把这些细胞都移植到了患有自身免疫性糖尿病的小鼠体内。细胞的“命运”截然不同:敲除Rnls基因的β细胞存活了下来;相反,保留了该基因的β细胞死去了。

科学家们又在培养皿中做了进一步观察,看一看面对免疫T细胞(它们也是自身免疫攻击的急先锋),这些缺乏Rnls基因的细胞会表现如何。结果令人惊喜,面对这种“改造版”β细胞,有一类T细胞“温柔”了许多,攻击性大打折扣。

那么,究竟是什么因素导致这种自身免疫性攻击被削弱?利用小鼠模型和人体细胞的研究进一步揭示了可能的细胞机制:敲除Rnls基因,有助于β细胞抵御内质网应激(ER stress),从而起到保护作用。

值得一提的是,尽管对于Rnls编码的蛋白有什么细胞功能人们还并不清楚,但是基于对这种蛋白晶体结构的认识,这支研究团队发现,有一种早在数十年前即已获得FDA批准的老药,即pargyline,有可能靶向结合RNLS蛋白,作为潜在的抑制剂。

给小鼠服用这款药物的实验结果,果然带来令人振奋的结果。在给移植β细胞的1型糖尿病小鼠喂食pargyline后,移植细胞不仅在数周时间内保持存活,还产生胰岛素并逆转了高血糖症状;相反,对照组的小鼠在移植β细胞后会很快失去移植的细胞,并保持高血糖状态。

服用pargyline后,1型糖尿病模型小鼠体内移植的胰岛β细胞可以存活更久,并改善血糖调节水平。

研究作者表示,鉴于这种药物已经得到FDA批准,他们希望接下来开展试点临床试验,看看在小鼠和人体细胞中观察到的保护作用是否适用于患者。

期待研究人员在后续研究中能够继续取得积极结果,开发出保护β细胞的新型药物,为全球1型糖尿病患者带来希望。

原始出处:

Erica P Cai, Yuki Ishikawa, Wei Zhang, et al.Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes.Nat Metab. 2020 Jul 27. doi: 10.1038/s42255-020-0254-1. Online ahead of print.

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GetPortalCommentsPageByObjectIdResponse(id=1618914, encodeId=7e2a1618914aa, content=<a href='/topic/show?id=007419239ca' target=_blank style='color:#2F92EE;'>#β细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19239, encryptionId=007419239ca, topicName=β细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b69919964433, createdName=ms24272190615788285182, createdTime=Thu Jul 30 23:52:23 CST 2020, time=2020-07-30, status=1, ipAttribution=)]
    2021-05-17 医者仁心
  4. 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    2021-05-06 一闲
  5. 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GetPortalCommentsPageByObjectIdResponse(id=1618914, encodeId=7e2a1618914aa, content=<a href='/topic/show?id=007419239ca' target=_blank style='color:#2F92EE;'>#β细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19239, encryptionId=007419239ca, topicName=β细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b69919964433, createdName=ms24272190615788285182, createdTime=Thu Jul 30 23:52:23 CST 2020, time=2020-07-30, status=1, ipAttribution=)]
    2021-03-13 guojianrong
  6. [GetPortalCommentsPageByObjectIdResponse(id=1989996, encodeId=2272198999647, content=<a href='/topic/show?id=3207e6735ae' target=_blank style='color:#2F92EE;'>#糖尿病治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76735, encryptionId=3207e6735ae, topicName=糖尿病治疗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e6a1280, createdName=zhanglin3079, createdTime=Mon Jul 12 12:52:23 CST 2021, time=2021-07-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1903413, encodeId=118a19034136a, content=<a href='/topic/show?id=e1b0583884b' target=_blank style='color:#2F92EE;'>#新方法#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58388, encryptionId=e1b0583884b, topicName=新方法)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c22f171, 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objectType=article, channel=null, level=null, likeNumber=139, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2020/05/03/fde601355f31ddd90bbbbea7f8a31c3e.jpg, createdBy=4c0d5325898, createdName=Dr.Orange←, createdTime=Wed Sep 02 21:59:48 CST 2020, time=2020-09-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1557510, encodeId=c930155e51041, content=<a href='/topic/show?id=7bec398e2e6' target=_blank style='color:#2F92EE;'>#哈佛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=39872, encryptionId=7bec398e2e6, topicName=哈佛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1c7014916331, createdName=amyloid, createdTime=Thu Jul 30 23:52:23 CST 2020, time=2020-07-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1618914, encodeId=7e2a1618914aa, content=<a href='/topic/show?id=007419239ca' target=_blank style='color:#2F92EE;'>#β细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19239, encryptionId=007419239ca, topicName=β细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b69919964433, createdName=ms24272190615788285182, createdTime=Thu Jul 30 23:52:23 CST 2020, time=2020-07-30, status=1, ipAttribution=)]
    2020-10-02 baoya
  7. 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  8. 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objectType=article, channel=null, level=null, likeNumber=139, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2020/05/03/fde601355f31ddd90bbbbea7f8a31c3e.jpg, createdBy=4c0d5325898, createdName=Dr.Orange←, createdTime=Wed Sep 02 21:59:48 CST 2020, time=2020-09-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1557510, encodeId=c930155e51041, content=<a href='/topic/show?id=7bec398e2e6' target=_blank style='color:#2F92EE;'>#哈佛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=39872, encryptionId=7bec398e2e6, topicName=哈佛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1c7014916331, createdName=amyloid, createdTime=Thu Jul 30 23:52:23 CST 2020, time=2020-07-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1618914, encodeId=7e2a1618914aa, content=<a href='/topic/show?id=007419239ca' target=_blank style='color:#2F92EE;'>#β细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19239, encryptionId=007419239ca, topicName=β细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b69919964433, createdName=ms24272190615788285182, createdTime=Thu Jul 30 23:52:23 CST 2020, time=2020-07-30, status=1, ipAttribution=)]
    2020-09-02 Dr.Orange←

    希望能早日攻克希望能早日攻克T1D

    0

  9. 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    2020-07-30 amyloid
  10. 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