Engineering gene expression noise to modulate the collective inflammatory response

工程基因表达噪音来调节集体炎症反应

• 批准号: 2231765
• 负责人: Kathryn Miller-Jensen
• 金额: $ 72.08万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2231765&HistoricalAwards=false
• 关键词: Engineering; gene; expression; noise; modulate

The significance of this project is to show how critical biological functions can be modified by synthetically engineering modest changes in the distribution of gene expression across cells, sometimes referred to as “noise”. While synthetic genetic engineering approaches are often used to change average gene expression, modulating noise is under-explored. In addition, this research seeks to improve the persistence of students in pursuing more advanced careers in science and engineering. Summer research internships in computational and molecular biology will be provided to local community college. This research will broadly impact the field of systems and synthetic biology by developing synthetic approaches to precisely modulate gene expression noise. The overall objective of this research is to systematically alter gene expression noise following activation of inflammatory signaling and demonstrate how it impacts collective cell activation of the inflammatory response in innate immune cells. The central hypothesis to be tested is that the chromatin environment at the promoter and RNA polymerase II regulation are major determinants of gene expression noise. These processes can be synthetically targeted to rationally alter cell-to-cell variability during transcription to change cell-population responses. This hypothesis is supported by preliminary data demonstrating that a promoter’s permissiveness for transcription affects transcriptional noise. To achieve the objectives of this research, CRISPR-Cas9 technology will be used to recruit epigenetic regulators to target promoters to alter gene expression noise. A mathematical model will also be developed to predict how specific molecular steps in transcription modulate noise. Finally, to explore the biological significance of modulating noise, these tools will be used to predict and test how altering transcript distributions changes the inflammatory response in a cell population.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目的意义在于展示如何通过综合工程改变细胞间基因表达分布（有时称为“噪音”）来改变关键的生物功能。虽然合成基因工程方法通常用于改变平均基因表达，但调节噪音的探索还不够。此外，这项研究旨在提高学生追求更高级的科学和工程职业的毅力。将向当地社区大学提供计算和分子生物学的暑期研究实习机会。这项研究将通过开发精确调节基因表达噪声的合成方法来广泛影响系统和合成生物学领域。这项研究的总体目标是系统地改变炎症信号激活后的基因表达噪音，并证明它如何影响先天免疫细胞炎症反应的集体细胞激活。要测试的中心假设是启动子处的染色质环境和 RNA 聚合酶 II 调节是基因表达噪声的主要决定因素。这些过程可以综合靶向，以合理地改变转录过程中细胞间的变异性，从而改变细胞群的反应。这一假设得到了初步数据的支持，表明启动子对转录的许可会影响转录噪音。为了实现这项研究的目标，CRISPR-Cas9技术将用于招募表观遗传调节因子来靶向启动子以改变基因表达噪音。还将开发一个数学模型来预测转录中的特定分子步骤如何调节噪音。最后，为了探索调节噪声的生物学意义，这些工具将用于预测和测试改变转录本分布如何改变细胞群中的炎症反应。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。