Tracing transcriptomic changes to uncover unknown roles of TZDs

追踪转录组变化以揭示 TZD 的未知作用

• 批准号: 8940520
• 负责人: Kyoung Jae Won
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-06 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8940520
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Alternative Splicing; Antidiabetic Drugs; Binding Sites; Bioinformatics; Brown Fat; Burn injury; Calories; Cataloging; Catalogs; Chemicals; Clinical; Data; Development; Diabetes Mellitus; Drug Targeting; Equilibrium; Event; Exposure to; Fatty acid glycerol esters; Genes; Genetic; Genetic Transcription; Heating; Human; Knowledge; Lead; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic Diseases; Methodology; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Prevention; Process; Property; Protein Isoforms; RNA; RNA Decay; RNA Sequences; RNA Splicing; RNA Stability; RNA chemical synthesis; Risk; Risk Factors; Role; Safety; Signal Pathway; Societies; Spliceosomes; System; Therapeutic; Thiazolidinediones; Time; Visit; base; cardiovascular risk factor; gain of function; genome-wide; global run on sequencing; in vivo; innovation; insulin sensitivity; knock-down; mRNA Stability; novel; novel strategies; public health relevance; research study; response; therapeutic target; transcriptome sequencing; transcriptomics; Adipocytes; Adipose tissue; Adverse effects; Alternative Splicing; Antidiabetic Drugs; Binding Sites; Bioinformatics; Brown Fat; Burn injury; Calories; Cataloging; Catalogs; Chemicals; Clinical; Data; Development; Diabetes Mellitus; Drug Targeting; Equilibrium; Event; Exposure to; Fatty acid glycerol esters; Genes; Genetic; Genetic Transcription; Heating; Human; Knowledge; Lead; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic Diseases; Methodology; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Prevention; Process; Property; Protein Isoforms; RNA; RNA Decay; RNA Sequences; RNA Splicing; RNA Stability; RNA chemical synthesis; Risk; Risk Factors; Role; Safety; Signal Pathway; Societies; Spliceosomes; System; Therapeutic; Thiazolidinediones; Time; Visit; base; cardiovascular risk factor; gain of function; genome-wide; global run on sequencing; in vivo; innovation; insulin sensitivity; knock-down; mRNA Stability; novel; novel strategies; public health relevance; research study; response; therapeutic target; transcriptome sequencing; transcriptomics

 DESCRIPTION (provided by applicant): Obesity, caused by excess calories stored as fat in white adipose tissue (WAT), is a major risk factor for metabolic disorders including type 2 diabetes. The discovery of fat-burning brown adipose tissue (BAT) in humans has raised the exciting possibility that BAT may be targeted to treat obesity and metabolic diseases. Thiazolidinediones (TZDs) can function to convert WAT into a "brown-like" state, and they have been used as a remedy for diabetes, but their clinical use has been limited because of serious side effects. A molecular understanding of TZD action will lead to the development of efficacious yet lower-risk drugs for metabolic disorders. In our preliminary studies, we observed widespread co-transcriptional splicing in nascent RNAs (GROseq). We found that TZDs regulate co-transcriptional splicing as well as the transcription levels of splicesomal genes. Interestingly, genes with altered co-transcriptional splicing ratios were associated with browning effect and PPAR signaling pathway. Based on these observations, we propose to study alternative splicing regulated by TZDs and determine the association with insulin sensitivity. Also, we recently found that TZDs re-distribute Med1 occupancy, a subunit of the Mediator. Interestingly, Med23, another subunit of the Mediator, regulates alternative splicing. Based on these observations, we aim to study if the mediator redistribution is associated with alternative splicing. Moreover, we further aim to study RNA stability by integrating nascent RNA (GROseq) and steady-state RNA (RNAseq). Isoforms spliced differently have different half-lives. Using a systematic way to integrate transcriptomic data we will investigate if TZDs regulate RNA stability. Our innovative approach to use nascent and steady-state RNAs will enhance our understanding of TZDs by fully exploiting the transcriptomic landscapes. The comprehensive nature of our study will reveal previously unrecognized regulatory mechanisms of TZDs in regulating alternative splicing and RNA stability. Our study will lead us to the identification of efficacious, low-risk drug targets fr the metabolic disorders that pervade society.

 描述（由适用提供）：肥胖，是由白脂肪组织（WAT）中储存为脂肪的过量卡路里引起的，是包括2型糖尿病在内的代谢疾病的主要危险因素。人类中燃烧脂肪脂肪组织（BAT）的发现提出了令人兴奋的可能性，即可能针对治疗肥胖症和代谢疾病的蝙蝠。噻唑烷二酮（TZD）可以将WAT转化为“棕色”状态，并且已被用作糖尿病的疗法，但是由于严重的副作用，它们的临床使用受到限制。对TZD作用的分子理解将导致为代谢疾病的有效而低风险的药物发展。在我们的初步研究中，我们观察到了新生RNA（Groseq）中宽度的共转录剪接。我们发现TZD调节共转录剪接以及香料膜基因的转录水平。有趣的是，共同转录剪接比改变的基因与褐变效应和PPAR信号通路有关。基于这些观察结果，我们建议研究由TZD调节的替代剪接，并确定与胰岛素敏感性的关联。另外，我们最近发现TZDS重新分发了Med1占用率，这是调解人的亚基。有趣的是，调解人的另一个亚基Med23调节替代剪接。基于这些观察结果，我们旨在研究介体重新分布是否与替代拼接有关。此外，我们进一步旨在通过整合新生RNA（Groseq）和稳态RNA（RNASEQ）来研究RNA稳定性。同工型剪接不同的半衰期不同。使用系统的方式集成转录组数据，我们将研究TZDS是否调节RNA稳定性。我们使用新生和稳态RNA的创新方法将通过充分利用转录组景观来增强我们对TZD的理解。我们研究的全面性质将揭示以前未被认可的TZD在调节性替代剪接和RNA稳定性中的调节机制。我们的研究将使我们确定有效的，低风险的药物靶标，而遍布社会的代谢障碍。