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.

该项目的广阔愿景是通过科学家（化学家、生物学家、医生和工程师）的跨领域合作，利用利用生物生命方法建立构建功能材料的巨大机会，为未来的生物制造开发新工具。用于活细胞、组织和动物内多种功能材料的基因靶向化学合成的生物制造工具箱，从长远来看，多种细胞特异性化学合成能够实现广泛的功能特性和组装结构。这些技术能够利用细胞内复杂的组装结构直接在生物系统内构建电子器件。应用这些技术来开发在大脑内创建新传导通路的能力可能会导致神经回路的重新布线。神经可能允许细胞特异性神经刺激和神经假体记录材料的进一步研究可能会导致治疗阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）等疾病，或选择性修复。尽管目前的工作仅侧重于基本工具的开发和对修饰对神经活动影响的初步了解，但这些工具有可能扩展到不同的细胞类型，用于治疗和创造新的细胞类型。该项目为参与研究的学生和博士后提供了直接的培训机会以及跨学科合作的重要技能，这些学员随后通过运行自己的独立研究小组进一步发展生物制造及其合作方法。该项目中的培训核心计划为数百名学生、教师和研究人员提供有关基本生物制造技术的实践培训。多细胞生命系统中的结构和功能复杂性水平仍然难以实现，将酶和其他蛋白质遗传靶向特定细胞类型的能力尚未被利用来指导生物系统整合的功能结构的复杂组装。的领域该项目以前所未有的方式结合分子遗传学、组织生物学、化学和材料科学来改变复杂结构的生物制造，重点是在活体的目标细胞类型中构建新颖的结构，创造天然和非天然的聚合物。这项工作的重点是开发和应用用于基因多样化目标合成过程的新型工具箱，同时进行生物相容性工程，表征合成的分子/材料，并了解其机制和影响。的该奖项由分子和细胞生物科学部、化学、生物工程、环境和运输系统部和化学部以及工业部共同资助。创新与合作伙伴关系、工程教育和中心部门以及材料研究部门。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

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

在活神经元膜上原位遗传靶向聚合物化学组装

• DOI: 10.1101/2022.12.27.521974
• 发表时间: 2022-12-27
• 期刊: bioRxiv
• 作者: Anqi Zhang;K. Y. Loh;Ch;an S. Kadur;an;Lukas Michalek;Jiayi Dou;C. Ramakrishnan;Zhenan Bao;K. Deisseroth
• 通讯作者: K. Deisseroth

Conjugated Polymer for Implantable Electronics toward Clinical Application

用于临床应用的植入式电子器件的共轭聚合物

• DOI: 10.1002/adhm.202001916
• 发表时间: 2021-04-25
• 期刊: Advanced Healthcare Materials
• 影响因子: 10
• 作者: Yuxin Liu;V. Feig;Z. Bao
• 通讯作者: Z. Bao

Genetically-encoded photosensitizers enable light-controlled polymerization on living neuronal membranes

基因编码的光敏剂能够在活神经元膜上进行光控聚合

• DOI: 10.1101/2022.12.27.521977
• 发表时间: 2022-12-27
• 期刊: bioRxiv
• 作者: Anqi Zhang;Ch;an S. Kadur;an;C. Ramakrishnan;Zhenan Bao;K. Deisseroth
• 通讯作者: K. Deisseroth

Genetically targeted chemical assembly of polymers specifically localized extracellularly to surface membranes of living neurons

聚合物的基因靶向化学组装专门位于活神经元的细胞外表面膜

• DOI: 10.1126/sciadv.adi1870
• 发表时间: 2023-08-09
• 期刊: Science Advances
• 影响因子: 13.6
• 作者: Zhang, Anqi;Loh, Kang Yong;Kadur, Chandan S. S.;Michalek, Lukas;Dou, Jiayi;Ramakrishnan, Charu;Bao, Zhenan;Deisseroth, Karl
• 通讯作者: Deisseroth, Karl