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RoL: EAGER: DESYN-C3: Synthetic Biogenesis of Eukaryotic Cells

RoL：EAGER：DESYN-C3：真核细胞的合成生物发生

基本信息

批准号：
1844299
负责人：
Don DeVoe
金额：
$ 30万
依托单位：
University of Maryland, College Park
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2021-09-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1844299&HistoricalAwards=false
关键词：
RoL EAGER DESYN C3 Synthetic

项目摘要

The nucleus is where a cell stores information. The endoplasmic reticulum (ER) is where cells manufacture proteins. Mitochondria are where cells generate energy. Designing cells to mimic human cells will likely involve replicating at least those core functions. This project will attempt to do just that. The project will involve artificial chromosomes being packaged into a compartment surrounded by a membrane, representing the nucleus. The nucleus will be surrounded by a folded membrane structure that mimics the ER. Inside the ER will be machinery to produce proteins. A separate membrane compartment, unattached to the other two, will house enzymes for generating energy. All of these will be contained in another membrane compartment and together, represent a crude synthetic cell. Creating the individual compartments will be challenging because the membranes have to allow some molecules to pass through them selectively while preventing others, and because some membranes will need to have intricate shapes. If the project is successful, it will provide a platform for subsequent efforts to use these types of synthetic cells to manufacture vaccines or to kill tumors, just to name a couple of possibilities. The project will involve a team of local high school students in all phases of the research through the International Genetically Engineered Machine (iGEM) competition.This project will develop the techniques needed to engineer cell-like structures, enabling the development of complex synthetic systems mimicking both structure and function of biological cells. There are two major tasks. First, microfluidic techniques will be employed to assemble a defined population of chromosomes within a discrete aqueous volume. A nuclear envelope will be formed around the chromosomes and interconnected with a folded ER-like membrane engineered using curvature-promoting proteins. Biological components extracted from cells will be integrated into the membrane. A nuclear lamina will be formed within the nucleus. Transcription of mRNA within the synthetic nuclei will then be demonstrated. Second, mitochondria-like structures will be developed to serve as ATP sources for mRNA transcription. A vesicle-based approach will support external control over mRNA transcription through mitochondria-nucleus ATP transport. This project will contribute to understanding the requirements for synthesizing and linking other cell-like organelles with increasing levels of complexity. That will create new opportunities for exploring open questions such as membrane how and why cells age. Synthetic cells could ultimately be exploited for closed loop control over DNA processing and gene regulation, with significant potential for practical biomedical applications including cancer immunotherapy.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.

细胞核是细胞存储信息的地方。内质网(ER)是细胞制造蛋白质的地方。线粒体是细胞产生能量的地方。设计细胞来模仿人类细胞可能至少涉及复制这些核心功能。这个项目将试图做到这一点。该项目将把人造染色体包装成一个隔间，由一层膜包围，代表细胞核。细胞核将被模拟内质网的折叠膜结构所包围。内质网内部将是生产蛋白质的机器。一个独立的隔膜隔间，与另外两个隔膜分离，将容纳产生能量的酶。所有这些都将被装在另一个膜室里，一起代表一个粗制的合成细胞。创建单独的隔室将是具有挑战性的，因为膜必须允许一些分子选择性地通过它们，同时防止其他分子通过，而且因为一些膜需要具有复杂的形状。如果该项目成功，它将为使用这些类型的合成细胞制造疫苗或杀死肿瘤的后续努力提供一个平台，仅举几个可能性。该项目将包括一个由当地高中生组成的团队，通过国际基因工程机器(IGEM)竞赛参与研究的各个阶段。该项目将开发设计类细胞结构所需的技术，使开发模拟生物细胞结构和功能的复杂合成系统成为可能。有两项主要任务。首先，微流控技术将被用来在离散的水体积内组装确定的染色体群体。核包膜将在染色体周围形成，并与使用曲率促进蛋白设计的折叠内质网样膜相互连接。从细胞中提取的生物成分将被整合到膜中。核内将形成一层核层。然后将演示合成细胞核内的mRNA转录。其次，线粒体样结构将被开发为mRNA转录的ATP来源。基于囊泡的方法将通过线粒体-细胞核ATP运输支持对mRNA转录的外部控制。该项目将有助于理解合成和连接复杂程度越来越高的其他细胞样细胞器的要求。这将为探索细胞膜如何以及为什么衰老等悬而未决的问题创造新的机会。合成细胞最终可能被用于DNA处理和基因调控的闭环控制，在包括癌症免疫治疗在内的实际生物医学应用中具有巨大的潜力。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。