Design and mathematical analysis of activating transcriptional amplifiers that enable modular temporal control in synthetic juxtacrine circuits

作     者：Calvin Lam 

作者机构：Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA. 

出 版 物：《Synthetic and Systems Biotechnology》 (合成和系统生物技术（英文）)

年 卷 期：2023年第8卷第4期

页      面：654-672页

核心收录：

学科分类：08[工学] 09[农学] 0901[农学-作物学] 0836[工学-生物工程] 090102[农学-作物遗传育种] 

基　　金：University of Nebraska Medical Center  UNMC 

主　　题：Synthetic biology Synthetic development Synthetic immunotherapy synNotch SNIPR Amplifiers Self-organization Temporal control Spatiotemporal control CAR T cell Synthetic receptors 

摘      要：The ability to control mammalian cells such that they self-organize or enact therapeutic effects as desired has incredible *** only would it further our understanding of native processes such as development and the immune response,but it would also have powerful applications in medical fields such as regenerative medicine and *** control is typically obtained by synthetic circuits that use synthetic receptors,but control remains *** synthetic juxtacrine receptors(SJRs)are widely used as they are fully modular and enable spatial control,but they have limited gene expression amplification and temporal *** these are integral facets to cell control,I therefore designed transcription factor based amplifiers that amplify gene expression and enable unidirectional temporal control by prolonging duration of target gene *** a validated in silico framework for SJR signaling,I combined these amplifiers with SJRs and show that these SJR amplifier circuits can direct spatiotemporal patterning and improve the quality of self-organization.I then show that these circuits can improve chimeric antigen receptor(CAR)T cell tumor killing against various heterogenous antigen expression *** amplifiers are flexible tools that improve control over SJR based circuits with both basic and therapeutic applications.