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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.

细胞核是细胞储存信息的地方。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。设计模仿人类细胞的细胞可能涉及至少复制这些核心功能。这个项目将试图做到这一点。该项目将涉及人工染色体被包装到一个由膜包围的隔室中，代表细胞核。细胞核将被模拟ER的折叠膜结构包围。在内质网内部将是生产蛋白质的机器。一个单独的膜室，不连接到其他两个，将容纳酶产生能量。所有这些将包含在另一个膜隔室中，并且一起代表粗合成细胞。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，同时阻止其他分子，并且因为一些膜需要具有复杂的形状。如果该项目成功，它将为后续使用这些类型的合成细胞制造疫苗或杀死肿瘤的工作提供一个平台，仅举几个可能性。该项目将通过国际基因工程机器（iGEM）竞赛，让一个由当地高中生组成的团队参与研究的各个阶段。该项目将开发设计细胞样结构所需的技术，从而能够开发模拟生物细胞结构和功能的复杂合成系统。有两项主要任务。首先，将采用微流体技术在离散的水性体积内组装限定的染色体群体。在染色体周围将形成一个核包膜，并与一个折叠的ER样膜相互连接，该膜使用曲率促进蛋白质工程化。从细胞中提取的生物成分将被整合到膜中。在细胞核内会形成一个核层。然后将证明合成核内mRNA的转录。第二，将开发出类ATP结构作为mRNA转录的ATP来源。基于囊泡的方法将支持通过胞核ATP转运对mRNA转录的外部控制。该项目将有助于理解合成和连接其他复杂程度不断增加的细胞样细胞器的要求。这将为探索诸如细胞膜如何以及为什么衰老等开放性问题创造新的机会。合成细胞最终可用于DNA加工和基因调控的闭环控制，在实际生物医学应用中具有巨大潜力，包括癌症免疫治疗。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。