Collaborative Research: Unraveling extracellular microRNA communication

合作研究：解开细胞外 microRNA 通讯

• 批准号: 2029121
• 负责人: Leonidas Bleris
• 金额: $ 62.37万
• 依托单位: University of Texas at Dallas
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2029121&HistoricalAwards=false
• 关键词: Collaborative; Research; Unraveling; extracellular; microRNA

The long-term goal of this project is to better understand how cells communicate with each other. This project focuses on the relatively unexplored process of cell-cell communication via microRNAs. A major roadblock to understanding microRNA-mediated cell-cell communication has been the inability to distinguish microRNAs produced by donor and recipient cells. This project will employ an innovative approach to get around this roadblock. The successful completion of this work will lead to a better understanding of microRNA-mediated cell-cell communication and a new set of resources and tools for investigating cell-cell interactions in a variety of organisms, including humans. The project will provide opportunities for graduate and undergraduate students to be exposed to an integrated research environment, combining theory and experiments at the intersection of biology and engineering. MicroRNAs (miRNAs) are small non-coding RNAs with significant regulatory roles in all physiological processes. miRNAs were thought to be stable only inside cells and rapidly degraded by enzymes when outside the cell. Recent work has demonstrated that this is not the case: cells can export miRNAs through multiple mechanisms, affecting other cells either next door or at great distances away. Past work has typically focused on one miRNA at a time because it is impossible to distinguish miRNA molecules made by one cell from those made by another. Major questions remain unanswered: Which miRNAs are transferred? What mechanisms do cells use to transfer them? To overcome hurdles and answer these questions, expertise in miRNA biology, synthetic biology and genome editing will be leveraged. Two features of non-mammalian systems will be adopted: a protozoan enzyme to label RNA, and CRISPR/Cas to engineer custom genetic circuits and introduce genome modifications. Combining cells engineered to label RNA with those that do not label RNA will enable the identification of miRNA species that are transferred between cells. Implementation and stable integration of custom synthetic biology circuits in human cells will permit the reliable monitoring of miRNA levels. Selective pharmacological blocking of inter-cellular communication mechanisms will facilitate the determination of how such transfer occurs. Genome editing will allow pinpointing which genes involved in specific transfer mechanisms are the critical determinants of miRNA exchange between cells. The long-term goal is to address questions about how cells communicate with each other. Successful completion of the proposed work will identify miRNAs that mediate cell-cell communication and generate a new set of resources and tools for investigating the relationship between cells in many different models of human biology.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.

该项目的长期目标是更好地了解细胞如何相互通信。 该项目着重于通过microRNA的细胞电池通信的相对未开发的过程。 了解microRNA介导的细胞 - 细胞通信的主要障碍是无法区分供体和受体细胞产生的microRNA。 该项目将采用一种创新的方法来解决此障碍。 这项工作的成功完成将使人们更好地了解MicroRNA介导的细胞 - 细胞通信，以及一套新的资源和工具，用于研究包括人类在内的各种生物中的细胞细胞相互作用。 该项目将为研究生和本科生提供机会，使其接触到综合研究环境，并将理论和实验结合在生物学与工程的交集中。 MicroRNA（miRNA）是在所有生理过程中具有重要调节作用的小型非编码RNA。 人们认为miRNA仅在细胞内部是稳定的，并且在细胞外面被酶迅速降解。 最近的工作表明，情况并非如此：细胞可以通过多种机制导出miRNA，从而影响隔壁或大距离的其他细胞。 过去的工作通常一次集中在一个miRNA上，因为不可能将一个细胞与另一个细胞制成的miRNA分子区分开。 主要问题仍未解决：哪些miRNA被转移？细胞使用哪些机制转移它们？为了克服障碍并回答这些问题，将利用miRNA生物学，合成生物学和基因组编辑方面的专业知识。非哺乳动物系统的两个特征将被采用：一种原生动物酶标记RNA，以及CRISPR/CAS来设计自定义遗传回路并引入基因组修饰。 将工程为RNA标记的细胞与不标记RNA标记的细胞相结合，可以鉴定在细胞之间转移的miRNA物种。 在人类细胞中定制合成生物学电路的实施和稳定整合将允许对miRNA水平的可靠监测。 细胞间通信机制的选择性药理阻断将有助于确定这种转移的发生方式。 基因组编辑将允许精确指出哪些与特定转移机制有关的基因是细胞之间miRNA交换的关键决定因素。 长期目标是解决有关细胞如何相互通信的问题。 成功完成拟议的工作将确定介导细胞电池通信的miRNA，并为许多不同的人类生物学模型中的细胞之间的关系生成新的资源和工具。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来支持的。

项目成果

Non-viral nitric oxide-based gene therapy improves perfusion and liposomal doxorubicin sonopermeation in neuroblastoma models.

• DOI: 10.7150/thno.81700
• 发表时间: 2023
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Bellary A;Nowak C;Iwanicki I;Flores-Guzman F;Wu L;Kandel JJ;Laetsch TW;Bleris L;Hernandez SL;Sirsi SR
• 通讯作者: Sirsi SR