BBSRC-NSF/BIO Deciphering the Rules of Nucleus Architecture with Synthetic Cells and Organelles

细胞生命的一个近乎普遍的方面是组成细胞的分子的空间分布不均匀，最常见的形式是亚细胞细胞器。真核细胞内的细胞器是细胞内明确定义的空间结构，专门用于执行确定的生化任务。技术上的限制意味着缺乏对管理细胞内隔间的基本原则的基本理解。在这个项目中，研究人员将使用合成细胞方法来解决这一疏忽，在合成细胞方法中，新的生物系统是由分子构件构建的。他们的假设是，合成细胞可以成为研究细胞器和细胞结构基础的独特而宝贵的工具。研究人员与伦敦帝国理工学院合作，正在开发一系列技术和建模工具，以解开合成细胞器的制造。具体地说，他们正在建立和使用合成系统来模仿真核生物的主要特征：核分离转录和翻译。组装可编程膜结构的能力，以及整合数学模型的能力，将使研究人员能够将合成细胞用作试验床，研究与细胞和核生物学有关的突出基本问题。这一合作项目包括两个社区目标，这两个目标利用了英国和美国对合成细胞及其创造、研究和应用的迅速增长的兴趣：(1)为Build-A-Cell(美国)和FabriCELL(英国)财团建立一座国际桥梁。这一合作将成为塑造各自社区的焦点，并确保实现从头开始建立合成细胞这一重大挑战所需的想法、专业知识和人员的交叉交流。(2)积极与生命科学、生物技术和微流体部门的受益者接触。这将通过一系列影响活动来实现，包括举办行业/学术视野扫描研讨会，出席会议和研讨会，并参加一系列外展活动。英国和美国专家团队的合作旨在实现五个科学目标和两个社区目标。科学目标将直接借鉴其研究组现有的试点工作：(1)开发微流体和膜工程工具以构建合成细胞器和核；(2)开发用于设计和分析区隔合成细胞的建模平台；(3)研究区隔对耦合生化过程的影响；(4)研究核内区隔对转录动力学的影响；(5)探索核：细胞质体积比的调节规则。前两个目标涉及构建和模拟合成细胞器的平台开发。最后三个目标涉及将我们的平台用于与细胞区隔的作用和细胞核的核心重要性相关的基础研究。这一美英合作项目由美国国家科学基金会(NSF)和英国生物技术和生物科学研究理事会(BBSRC)支持，其中NSF资助美国的研究人员，BBSRC资助英国的合作伙伴。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。

A near-universal aspect of cellular life is the non-uniform spatial distribution of molecules that make up cells, which most often takes the form of sub-cellular organelles. Organelles within eukaryotic cells are well defined spatial structures within cells that are specialized to perform defined biochemical tasks. Technological limitations have meant that the fundamental understanding of the underpinning principles that govern compartmentalization in cells is lacking. In this project, the investigators will address this oversight using a synthetic cell approach where new biological systems are constructed from molecular building blocks. Their hypothesis is that synthetic cells can become a unique and invaluable tool to study the fundamentals of organelles and cellular architectures. Working with Imperial College London, the investigators are developing a series of technologies and modeling tools that unlock the manufacture of synthetic organelles. Specifically, they are building and using synthetic systems to mimic the dominant feature of eukaryotes: the segregation of transcription and translation by the nucleus. The ability to assemble programmable membrane architectures, as well as integrating mathematical models, will allow the investigators to use the synthetic cells as a testbed to investigate outstanding fundamental questions relating to cell and nucleus biology. Included in this collaborative project are two community objectives that leverage the rapidly emerging interest in synthetic cells, their creation, study and applications in both the UK and the USA: (1) Build an international bridge for the Build-A-Cell (USA) and fabriCELL (UK) consortia. This collaboration will serve as a focal point to shape the respective communities and ensure the cross-fertilisation of ideas, expertise, and personnel that is needed to achieve the grand challenge of building a synthetic cell from scratch. (2) Actively engage with beneficiaries in the life sciences, biotechnology, and microfluidics sectors. This will be achieved through a series of impact activities, including organising an industry/academic horizon scanning workshop, attending conferences and symposia, and participating in a host of outreach activities. The collaborative work between expert UK and US teams is designed to achieve five scientific objectives and two community objectives. The scientific objectives will directly build from existing pilot work in their research groups: (1) develop microfluidic and membrane engineering tools to build synthetic organelles and nuclei; (2) develop modeling platforms for the design and analysis of compartmentalized synthetic cells; (3) examine the effects of compartmentalization on coupled biochemical processes; (4) investigate how transcription dynamics are affected by compartmentalization in a nucleus; (5) explore rules governing the nucleus: cytoplasm volume ratio. The first two objectives involve platform development for constructing and modelling synthetic organelles. The final three objectives involve using our platforms in fundamental studies relating to the role of cellular compartmentalisation and the central importance of the cell’s nucleus.This collaborative US/UK project is supported by the US National Science Foundation (NSF) and the UK Biotechnology and Biological Sciences Research Council (BBSRC), where NSF funds the US investigator and BBSRC funds the partners in the UK.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.