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Gene therapy for diabetes using liganded-thyroid hormone receptor

使用配体甲状腺激素受体治疗糖尿病的基因疗法

基本信息

批准号：
22790883
负责人：
FURUYA Fumihiko
金额：
$ 2.41万
依托单位：
University of Yamanashi
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

项目摘要

One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that liganded thyroid hormone receptorα(TRα) plays a critical role in expansion of theβ-cell mass during postnatal development.AdTRαis a recombinant adenoviral vector that expresses human TRα1 under the control of the cytomegalovirus promoter. To analyze whether TRαgene transfer induces reprogramming of pancreatic exocrine cells to insulin-producing cells, AdTRαwere injected into the pancreas of immunodeficient mice. Rat pancreatic AR42J cells that possess exocrine and neuroendocrine properties were infected with AdTRα. The expression of transcription factors that are involved in the differentiation of pancreatic endocrine cells was then analyzed by quantitative RT-PCR, western blot or immunocytochemistry. To explore whether liganded-TRα-induced reprogramming of pancreatic exocrine cells is direct or indirect effect, AdTRα-infected AR42J cells were concomitantly transfected with siRNA of Ngn3 or MafA.Small scattered clusters of insulin-producing cells, which also expressed lipase, were observed in AdTRα-infected mice. T3-treatment of AR42J cells that were infected with AdTRαand pretreated with activin A increased the mRNA and protein expression levels of Ngn3 and MafA, compared to no T3-treatment. Overexpression of TRαtogether with T3-treatment also induced insulin expression in activin A-treated AR42J cells. The siRNA-induced inhibition of expression of Ngn3 or MafA significantly inhibited AdTRα-induced reprogramming of AR42J cells into insulin-producing cells.Conclusions : These results suggested that combination of liganded-TRαand activin A leads to reprogramming pancreatic exocrine cells to insulin-producing cells via induction of Ngn3 and MafA. Our findings also support the hypothesis that liganded-TRαplays a critical role inβ-cell regeneration during postnatal development.

糖尿病再生医学的一个目标是将成熟的胰腺外分泌细胞转化为胰岛素产生细胞。我们最近报道了配体甲状腺激素受体α（liganded thyroid hormone receptor α，TRα 1）在出生后β细胞团的扩增中起关键作用，AdTRα是一种在巨细胞病毒启动子控制下表达人TRα1的重组腺病毒载体。为了分析TRα基因转移是否诱导胰腺外分泌细胞重编程为胰岛素产生细胞，将AdTRα注射到免疫缺陷小鼠的胰腺中。用AdTRα感染具有外分泌和神经内分泌特性的大鼠胰腺AR 42 J细胞。然后通过定量RT-PCR、蛋白质印迹或免疫细胞化学分析参与胰腺内分泌细胞分化的转录因子的表达。为了探讨配体TR α诱导胰腺外分泌细胞重编程的作用是直接还是间接的，我们同时用Ngn 3或MafA的siRNA转染AdTRα感染的AR 42 J细胞，在AdTRα感染的小鼠中观察到了小的散在的胰岛素分泌细胞簇，这些细胞也表达脂肪酶。用AdTRα感染并用激活素A预处理的AR 42 J细胞的T3处理与未处理相比增加Ngn 3和MafA的mRNA和蛋白表达水平。过表达TRα与T3处理一起也诱导激活素A处理的AR 42 J细胞中胰岛素表达。结论：重组腺病毒介导的AR 42 J细胞重编程是通过Ngn 3和MafA的诱导而实现的。我们的研究结果也支持了这一假设，即配体TR α在出生后发育过程中的β细胞再生中起着关键作用。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes.

DOI：
10.2337/db10-0795
发表时间：
2011-03
期刊：
Diabetes
影响因子：
7.7
作者：
Aida K;Nishida Y;Tanaka S;Maruyama T;Shimada A;Awata T;Suzuki M;Shimura H;Takizawa S;Ichijo M;Akiyama D;Furuya F;Kawaguchi A;Kaneshige M;Itakura J;Fujii H;Endo T;Kobayashi T
通讯作者：
Kobayashi T

RIGI- and MDA5-Initiated Innate Immunity Linked With Adaptivelmmunity Accelerates{beta}-Cell Death in Fulminant Type 1 Diabetes.

RIGI 和 MDA5 启动的先天免疫与适应性免疫相关，加速暴发性 1 型糖尿病中的 {β}-细胞死亡。