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Synthetic toolkit for precision gene expression control and signal processing in mammalian cells

用于哺乳动物细胞中精确基因表达控制和信号处理的合成工具包

基本信息

批准号：
10584605
负责人：
Ahmad Samir Khalil
金额：
$ 67.5万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584605
关键词：
Address Adoption Advanced Development Autoimmunity Behavior Biochemical Biological Biological Process Biomedical Engineering Biomedical Research Cell Differentiation process Cell Reprogramming Cell Therapy Cells Cellular immunotherapy Chemicals Communities Complex Cues Custom Development Disease Dose Drug Design Enabling Factors Engineering FDA approved Fostering Gene Activation Gene Expression Generations Genes Genetic Transcription Goals Human Human Biology Human Engineering Immune Immunologist Ligands Malignant Neoplasms Mammalian Cell Methods Modeling Oncoproteins Organoids Output Pharmaceutical Preparations Physiology Play Process Property Publishing Regenerative Medicine Regulation Reporter Research Personnel Role Scheme Science Scientist Shapes Signal Transduction Specificity Stimulus System Technology Therapeutic Tissue Engineering Tissues Transcriptional Regulation Viral Vector Work Yeasts cell behavior cellular engineering combinatorial cytokine design flexibility gene product improved information processing interest notch protein novel novel diagnostics novel therapeutics programs response self assembly signal processing spatiotemporal synthetic biology therapy development tool transcription factor tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Cells activate precise gene expression programs in response to multifactorial chemical and biological stimuli. The purposeful manipulation of this process is a principal goal of synthetic biology, and its application to human cells could lead to breakthroughs in our understanding of human biology and in the development of next-generation diagnostics and therapeutics that respond in sophisticated ways to disease. Unfortunately, tools to artificially control gene expression in mammalian cells have significant limitations, constraining our ability to study fundamental biological processes and design more effective cell-based therapies. The most widely-used tools are older generation technology, derived from bacterial transcriptional systems. These are greatly limited in number, which restricts the number of gene products that can be simultaneously controlled. Additionally and importantly, they use “simple” one-to-one regulatory interactions, imposing fundamental restrictions on the regulatory flexibility and sophistication of designer systems. As a consequence, researchers are unable to create sophisticated gene expression controllers that can flexibly sense and integrate biochemical signals (e.g. ligands, chemical inducers, disease cues), and tune or reshape corresponding gene activation profiles. Among the many biomedical applications that would be transformed by these precision gene expression controllers in mammalian cells is the development of cell-based therapeutics for cancer, auto- immunity, and regenerative medicine, which can suffer from issues related to over-activation and tissue specificity. We propose to overcome these barriers by developing a novel synthetic toolkit for gene expression control in mammalian cells. Inspired by the natural design of metazoan transcriptional systems, our framework is based on synthetic transcription factors (synTFs) that can be programmed to assemble cooperatively in multivalent complexes. Our previous work showed that cooperative synTFs enable construction of gene expression control circuits with greatly expanded signal processing behavior in yeast. Here we will develop and characterize mammalian self-assembling synTFs that have superior properties for installation into human cells relative to existing tools. We will use these tools to develop three classes of gene expression controllers, which we will demonstrate in human immune cells, chosen for their important role in human physiology and their potential for cellular therapy: (1) Inducible controllers regulated by orthogonal, FDA-approved drugs. (2) Cell- autonomous controllers that sense and process biological stimuli, including ligand recognition by synthetic Notch receptors and microenvironmental cues. (3) Signal integration controllers that can perceive and integrate multiple biological signals to activate transcriptional programs. We anticipate that this toolkit will be broadly used by researchers to enable precision gene expression control across mammalian systems, including in biomedical applications of synthetic biology, cell reprogramming, and cell-based therapeutics. We will make our tools and design framework freely available to the academic scientific community.

项目总结/文摘

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.

人类疱疹病毒 8 ORF57 蛋白能够减少 TDP-43 病理：网络分析确定了相互作用的途径。

DOI：
10.1093/hmg/ddad122
发表时间：
2023
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Webber,ChelseaJ;Murphy,CarolineN;Rondón-Ortiz,AlejandroN;vanderSpek,SophieJF;Kelly,ElenaX;Lampl,NoahM;Chiesa,Giulio;Khalil,AhmadS;Emili,Andrew;Wolozin,Benjamin
通讯作者：
Wolozin,Benjamin

Synthetic biology in the clinic: engineering vaccines, diagnostics, and therapeutics.