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

 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（由申请人提供）：肥胖是由白色脂肪组织 (WAT) 中以脂肪形式储存的过量热量引起的，是包括 2 型糖尿病在内的代谢紊乱的主要危险因素。在人体中发现了燃烧脂肪的棕色脂肪组织 (BAT)。人类提出了令人兴奋的可能性，即 BAT 可能有针对性地治疗肥胖和代谢疾病，噻唑烷二酮类药物 (TZD) 可以将 WAT 转化为“棕色”状态，并且它们已被使用。作为糖尿病的治疗方法，但由于严重的副作用，对 TZD 作用的分子了解将有助于开发有效且风险较低的代谢性疾病药物。在我们的初步研究中，我们观察到广泛的副作用。 -新生RNA中的转录剪接（GROseq）我们发现TZD调节共转录剪接以及剪接体基因的转录水平。基于这些观察，我们建议研究 TZD 调节的选择性剪接并确定与胰岛素敏感性的关系。此外，我们最近发现 TZD 重新分配 Med1 占据（Med1 的一个亚基）。介体匿名，Med23，介体的另一个亚基，调节选择性剪接。基于这些观察，我们的目的是研究介体重新分布是否与选择性剪接相关。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，不同剪接的异构体具有不同的半衰期，我们将研究 TZD 是否具有调节作用。 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。我们研究的综合性质将揭示以前未被认识的调控机制。 TZD 在调节选择性剪接和 RNA 稳定性方面的作用将引导我们识别出针对社会普遍存在的代谢紊乱的有效、低风险的药物靶点。