Transcription cycle regulation by nutrients

营养物质的转录周期调节

基本信息

  • 批准号:
    10661045
  • 负责人:
  • 金额:
    $ 35.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-15 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated global prevalence of 1 in 4 individuals. No FDA-approved treatments are available. Aberrant transcriptional control of gene expression is central to the pathophysiology of metabolic diseases. Transcription by RNA Polymerase II (RNAP2) occurs through several coordinated steps, which include pre-initiation complex formation and initiation, elongation, and termination. The assembly of the basal transcription machinery and transcription initiation was believed for many years to be the rate-limiting and most important aspect driving gene expression. Recent research has revealed that the transition from initiation to elongation is a rate-limiting and critical step, requiring specific signals to release RNAP2 from its paused state and engage in transcription elongation. RNAP2 pause-release is a mechanism that allows fast and synchronized gene expression in response to environmental cues, adjusting expression of entire gene programs. The process of pause-release requires histone H3 acetylation at lys9 (H3K9ac) in the promoter-proximal region. H3K9ac levels are significantly altered by high-fat feeding in mice, a model of diet-induced obesity, insulin resistance and NAFLD. We hypothesize that RNAP2 pause-release is a fundamental mechanism of gene regulation in response to nutrient availability, and under conditions of nutrient excess, misregulated pause-release contributes to aberrant changes in gene expression. To study how cells respond to nutrients at the genome-wide level, high- throughput sequencing technologies will be used. The goals of this proposal will be achieved by pursuing the following specific aims: (i) Define the role of RNAP2 pause-release in transcription regulation in the fasted to refed transition; (ii) Determine the mechanism by which the pro-lipogenesis transcription factor Sterol Regulatory Element Binding Protein 1 (SREBP-1) contributes to regulate transcription elongation; (iii) Determine how H3K9ac contributes to change gene expression under high-fat conditions. This proposal is significant because it will identify a novel node of transcription regulation, breaking new ground for drug target discovery. Thus, this proposal addresses a basic scientific gap in the field of metabolism, and the results of these innovative studies could lead to the development of new and effective therapeutic interventions for NAFLD, type 2 diabetes and other associated metabolic diseases.
项目概要 非酒精性脂肪性肝病(NAFLD)是最常见的慢性肝病,据估计, 全球患病率为四分之一。没有 FDA 批准的治疗方法。转录异常 基因表达的控制是代谢疾病病理生理学的核心。 RNA转录 聚合酶 II (RNAP2) 通过几个协调步骤发生,其中包括预起始复合物 形成和起始、延伸和终止。基础转录机器的组装和 多年来,转录起始被认为是驱动速度的限制因素和最重要的方面 基因表达。最近的研究表明,从起始到延伸的转变是一个速率限制 关键步骤,需要特定信号将 RNAP2 从暂停状态释放并参与转录 伸长。 RNAP2暂停-释放是一种允许快速、同步基因表达的机制 对环境线索的反应,调整整个基因程序的表达。暂停-释放过程 需要启动子近端区域的 lys9 (H3K9ac) 处的组蛋白 H3 乙酰化。 H3K9ac 水平为 小鼠的高脂肪喂养显着改变了小鼠的饮食诱导肥胖、胰岛素抵抗和 NAFLD 模型。 我们假设 RNAP2 暂停释放是基因调控响应的基本机制 营养物质的可用性,并且在营养物质过量的情况下,错误调节的暂停释放会导致 基因表达的异常变化。为了研究细胞如何在全基因组水平上对营养物质做出反应,高 将使用通量测序技术。本提案的目标将通过追求以下目标来实现 以下具体目标: (i) 定义 RNAP2 暂停释放在禁食中转录调节中的作用 重新引用过渡; (ii) 确定促脂肪生成转录因子甾醇的作用机制 调节元件结合蛋白 1 (SREBP-1) 有助于调节转录延伸; (三) 确定 H3K9ac 如何在高脂肪条件下改变基因表达。这个提议是 意义重大,因为它将识别转录调控的新节点,为药物靶点开辟新天地 发现。因此,该提案解决了新陈代谢领域的基本科学空白,并且结果 这些创新研究可能会导致开发新的有效治疗干预措施 NAFLD、2 型糖尿病和其他相关代谢性疾病。

项目成果

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NURIA MORRAL其他文献

NURIA MORRAL的其他文献

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{{ truncateString('NURIA MORRAL', 18)}}的其他基金

Hepatic expression of small hairpin RNA using gutless adenoviral vectors
使用无肠腺病毒载体肝脏表达小发夹 RNA
  • 批准号:
    8467899
  • 财政年份:
    2008
  • 资助金额:
    $ 35.06万
  • 项目类别:
Hepatic expression of small hairpin RNA using gutless adenoviral vectors
使用无肠腺病毒载体肝脏表达小发夹 RNA
  • 批准号:
    8063970
  • 财政年份:
    2008
  • 资助金额:
    $ 35.06万
  • 项目类别:
Hepatic expression of small hairpin RNA using gutless adenoviral vectors
使用无肠腺病毒载体肝脏表达小发夹 RNA
  • 批准号:
    8250468
  • 财政年份:
    2008
  • 资助金额:
    $ 35.06万
  • 项目类别:
Hepatic expression of small hairpin RNA using gutless adenoviral vectors
使用无肠腺病毒载体肝脏表达小发夹 RNA
  • 批准号:
    7596980
  • 财政年份:
    2008
  • 资助金额:
    $ 35.06万
  • 项目类别:
Hepatic expression of small hairpin RNA using gutless adenoviral vectors
使用无肠腺病毒载体肝脏表达小发夹 RNA
  • 批准号:
    7800468
  • 财政年份:
    2008
  • 资助金额:
    $ 35.06万
  • 项目类别:
RNA Interference using gutless adenoviral vectors
使用无肠腺病毒载体进行 RNA 干扰
  • 批准号:
    6950365
  • 财政年份:
    2004
  • 资助金额:
    $ 35.06万
  • 项目类别:
RNA Interference using gutless adenoviral vectors
使用无肠腺病毒载体进行 RNA 干扰
  • 批准号:
    6849369
  • 财政年份:
    2004
  • 资助金额:
    $ 35.06万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    8874376
  • 财政年份:
  • 资助金额:
    $ 35.06万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    9282432
  • 财政年份:
  • 资助金额:
    $ 35.06万
  • 项目类别:

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