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Role of miR-30d in insulin gene expression in pancreatic beta cells

miR-30d 在胰腺β细胞胰岛素基因表达中的作用

基本信息

批准号：
8251702
负责人：
Xiaoqing Tang
金额：
$ 5.94万
依托单位：
MICHIGAN TECHNOLOGICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8251702
关键词：
Role miR 30d insulin gene

项目摘要

DESCRIPTION (provided by applicant): My long-term goal is to study the role of microRNAs (miRNAs) in regulating beta-cell function and to elucidate the role of miRNAs in the development of type-II diabetes. MiRNAs are small noncoding ribonucleotides that bind mRNAs and function mainly as translational repressors in mammals. miRNAs have been implicated to play a role in many diseases, including diabetes. Several reports indicate an important function for miRNAs in insulin secretion and pancreatic beta cell development. We have recently carried out a screen in the pancreatic beta cell line MIN6 to identify miRNAs with altered abundance in response to changes in glucose concentrations. This screen resulted in identification of more than 50 glucose-regulated miRNAs from a total of 108 miRNAs detectable in MIN6 cells. Many of the identified miRNAs, including miR-124a, miR-107 and miR-30d were upregulated in the presence of high glucose. Interestingly, we found that overexpression of miR-30d increased insulin gene transcription. Moreover, the induction of insulin by overexpression of miR-30d is associated with increased expression of the beta-cell specific transcription factor MafA. This suggests that the putative target genes of miR-30d may be negative regulators of MafA/insulin gene expression. To determine the function of miR-30d in insulin gene transcription, I will: 1) Identify miR-30d target genes involved in regulation of insulin gene transcription. 2) Characterize the biological function of miR-30d in pancreatic beta cell lines and primary mouse islets. The verified targets will be analyzed for their role in insulin gene expression by siRNA knock-down techniques. Moreover, the effect of miR-30d on the target downstream signaling will be characterized. Finally, the function of miR-30d in primary mouse islets will be confirmed using a recombinant adenovirus expressing miR-30d. The finding from this proposal will contribute to our understanding of miRNA function in insulin gene transcription. PUBLIC HEALTH RELEVANCE: Developing new approaches to restore insulin production and secretion from pancreatic beta cells is a major goal in diabetes research. MiR-30d is particularly interesting since our preliminary results indicate that it induces glucose-stimulated insulin gene expression. My objective in this proposal is to identify miR30d target genes and to characterize their function in insulin production. Taking into account that miR-30d also induces MafA expression, this miRNA emerges as an important target that may be beneficial in enhancing islet function and may thus aid in the design of alternative therapies for the prevention and treatment of diabetes.

描述（由申请人提供）：我的长期目标是研究 microRNA (miRNA) 在调节 β 细胞功能中的作用，并阐明 miRNA 在 II 型糖尿病发展中的作用。 miRNA 是一种小型非编码核糖核苷酸，可与 mRNA 结合，在哺乳动物中主要充当翻译抑制因子。 miRNA 在包括糖尿病在内的许多疾病中发挥着重要作用。一些报告表明 miRNA 在胰岛素分泌和胰腺 β 细胞发育中具有重要功能。我们最近在胰腺 β 细胞系 MIN6 中进行了筛选，以鉴定丰度随葡萄糖浓度变化而改变的 miRNA。该筛选从 MIN6 细胞中可检测到的总共 108 个 miRNA 中鉴定出了 50 多个葡萄糖调节的 miRNA。许多已鉴定的 miRNA，包括 miR-124a、miR-107 和 miR-30d 在高葡萄糖存在下上调。有趣的是，我们发现 miR-30d 的过度表达增加了胰岛素基因的转录。此外，miR-30d 过表达诱导胰岛素与 β 细胞特异性转录因子 MafA 表达增加相关。这表明 miR-30d 的推定靶基因可能是 MafA/胰岛素基因表达的负调节因子。为了确定 miR-30d 在胰岛素基因转录中的功能，我将： 1) 鉴定参与胰岛素基因转录调节的 miR-30d 靶基因。 2) 表征 miR-30d 在胰腺 β 细胞系和原代小鼠胰岛中的生物学功能。将通过 siRNA 敲低技术分析经过验证的靶标在胰岛素基因表达中的作用。此外，还将表征 miR-30d 对靶标下游信号传导的影响。最后，将使用表达 miR-30d 的重组腺病毒来证实 miR-30d 在原代小鼠胰岛中的功能。该提案的发现将有助于我们了解 miRNA 在胰岛素基因转录中的功能。公共健康相关性：开发新方法来恢复胰腺β细胞的胰岛素产生和分泌是糖尿病研究的一个主要目标。 MiR-30d 特别有趣，因为我们的初步结果表明它诱导葡萄糖刺激的胰岛素基因表达。我在此提案中的目标是鉴定 miR30d 靶基因并表征其在胰岛素产生中的功能。考虑到 miR-30d 也诱导 MafA 表达，该 miRNA 成为可能有益于增强胰岛功能的重要靶标，因此可能有助于设计预防和治疗糖尿病的替代疗法。