FMRG: Genetically-targeted chemical assembly (GTCA) of functional structures in living cells, tissues, and animals

FMRG：活细胞、组织和动物功能结构的基因靶向化学组装 (GTCA)

• 批准号: 2037164
• 负责人: Zhenan Bao
• 金额: $ 375万
• 依托单位: Stanford University
• 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: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2037164&HistoricalAwards=false
• 关键词: FMRG; Genetically; targeted; chemical; assembly

The broad vision for this project is to develop new tools for future biomanufacturing through cross-cutting collaborations of scientists—chemists, biologists, physicians, and engineers—united by the immense opportunity of building functional materials with, and within, biological life. The proposed methodologies establish the biomanufacturing toolbox for genetically-targeted chemical synthesis of a variety of functional materials within living cells, tissues and animals. Diverse cell-specific chemical syntheses enable a broad array of functional characteristics and assembled structures. In the long term, such techniques enable building electronics directly within biological systems by harnessing the complex assembly structures within cells. The application of these techniques to develop the capability to create new conductive pathways within the brain may lead to rewiring of neural circuits. Moreover, genetically-targeting the peripheral nerve may allow cell-specific nerve stimulation and recording for neuroprosthesis. Further investigation of the deposited material on neural activity may lead to treatments for diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), or selectively repair demyelinated areas for treatment of multiple sclerosis (MS). Even though current work only focuses on basic tool development and initial understanding of the impact of the modifications on neural activities, the tools can be potentially expanded to diverse cell types for therapeutics and creation of new materials and assemblies. This project offers direct training opportunities for the students and postdocs involved in terms of research as well as important skills for interdisciplinary collaboration. These trainees subsequently further the development of biomanufacturing and their method of collaboration by running their own independent research groups in academia or by incorporating their knowledge into future industrial developments. A Training Core program in this project provides hands-on training on basic biomanufacturing techniques for hundreds of students, instructors and researchers.Despite existing ability to engineer materials with diverse form and functionality, a high-level of structural and functional complexity found in multicellular living systems are still challenging to realize. The capability of genetically targeting enzymes and other proteins to specific cell types has yet to be harnessed to direct complex assembly of functional structures instructed by biological systems. This project integrates the fields of molecular genetics, tissue biology, chemistry, and materials science in unprecedented ways to transform the biomanufacturing of complex structures. The project focuses on building novel structures in vivo, creating natural and unnatural polymers within targeted cell-types of living organisms. This approach is extended to the development of a universal shared methodology for targeted chemistry within living beings. The work proposed focuses on developing and applying novel toolboxes for diverse genetically-targeted synthetic processes while engineering for biocompatibility, characterizing the synthesized molecules/materials, and understanding the mechanisms and implications of forming synthetic materials for eliciting natural and novel biological functions. This award is co-funded by the Division of Molecular and Cellular Biosciences, the Division of Chemical, Bioengineering, Environmental and Transport Systems and the Division of Chemistry, and also by the Division of Industrial Innovation and Partnerships, the Division of Engineering Education and Centers, and the Division of Materials Research.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.

该项目的广阔前景是通过科学家化学家，生物学家，医生和工程师的跨领域合作，为未来的生物制造开发新的工具，这些科学家通过与生物生命一起构建功能材料的巨大机会团结在一起。所提出的方法建立了生物制造工具箱，用于在活细胞、组织和动物内进行各种功能材料的遗传靶向化学合成。不同的细胞特异性化学合成能够实现广泛的功能特征和组装结构。从长远来看，这种技术能够通过利用细胞内复杂的组装结构直接在生物系统内构建电子产品。应用这些技术来开发在大脑内创建新的传导通路的能力可能会导致神经回路的重新布线。此外，遗传靶向外周神经可以允许细胞特异性神经刺激和记录神经假体。对沉积的材料对神经活动的进一步研究可能导致对诸如阿尔茨海默病（AD）和肌萎缩侧索硬化（ALS）的疾病的治疗，或选择性地修复脱髓鞘区域以治疗多发性硬化（MS）。尽管目前的工作只集中在基本的工具开发和初步了解修改对神经活动的影响，但这些工具可以扩展到不同的细胞类型，用于治疗和创造新材料和组件。该项目为参与研究的学生和博士后提供直接培训机会，并为跨学科合作提供重要技能。这些学员随后通过在学术界运行自己的独立研究小组或将其知识融入未来的工业发展，进一步发展生物制造及其合作方法。该项目中的培训核心项目为数百名学生、教师和研究人员提供了基本生物制造技术的实践培训。尽管现有的能力可以设计具有不同形式和功能的材料，但在多细胞生命系统中发现的高水平结构和功能复杂性仍然具有挑战性。将酶和其他蛋白质遗传靶向到特定细胞类型的能力尚未被利用来指导由生物系统指示的功能结构的复杂组装。该项目以前所未有的方式整合了分子遗传学，组织生物学，化学和材料科学领域，以改变复杂结构的生物制造。该项目的重点是在体内构建新的结构，在活生物体的目标细胞类型中创建天然和非天然聚合物。这种方法被扩展到生物体内目标化学的通用共享方法的开发。这项工作的重点是开发和应用新的工具箱，用于不同的基因靶向合成过程，同时进行生物相容性工程，表征合成的分子/材料，并了解形成合成材料的机制和影响，以激发天然和新型生物功能。该奖项由分子和细胞生物科学司，化学，生物工程，环境和运输系统司和化学司共同资助，并由工业创新和伙伴关系司，工程教育和中心司，该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的学术价值和更广泛的影响审查标准。

项目成果

In situ genetically targeted chemical assembly of polymers on living neuronal membranes

• DOI: 10.1101/2022.12.27.521974
• 发表时间: 2022-12
• 期刊: bioRxiv
• 作者: Anqi Zhang;K. Y. Loh;Chandan S. Kadur;Lukas Michalek;Jiayi Dou;C. Ramakrishnan;Zhenan Bao;K. Deisseroth