Citation
Zhu, Ronghui (2023) Multicellular Circuit Design in Mammalian Cells. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/p0fn-qa56. https://resolver.caltech.edu/CaltechTHESIS:07252022-061122576
Abstract
Multicellular circuits control the development of multicellular organisms, through programming processes such as cell proliferation, cell differentiation, cell movement, and cell signaling. A fundamental goal of biology is to understand the design principles of these multicellular circuits, and use these principles to design synthetic multicellular systems for therapeutic purposes. Top-down approaches, for example analyzing embryos bearing genetic mutations, have identified key genes in many multicellular circuits, but are challenging to study these circuits in an isolated context and in a quantitative and systematic manner. An alternative, complementary approach is to engineer or reconstitute multicellular circuits from bottom-up, which allows us to overcome the limitations of top-down approach and gain quantitative insights into multicellular circuit design. In this thesis, we use this bottom-up approach to explore the design principles of two multicellular circuits. In the first project, we took inspiration from two prevalent features from natural multistable circuits, namely competitive protein-protein interactions and positive autoregulation, to design a synthetic multistable circuit architecture called MultiFate. Both in the model and in the experiment, MultiFate circuits generate multiple cellular states, each stable for weeks, allow control over state-switching and state stability, and can be easily expanded to generate more states. In the second project, we use a gradient reconstitution system to systematically analyze a gradient modulation circuit consisting of BMP4 and its modulators, Chordin, Twsg and BMP-1. We found that the circuit can give rise to diverse gradient modulation capabilities. In particular, the full circuit is sufficient for active ligand shuttling and generation of non-monotonic displaced gradient. These multicellular circuits could provide a foundation for engineering synthetic multicellular systems in mammalian cells.
Item Type: | Thesis (Dissertation (Ph.D.)) | ||||||
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Subject Keywords: | Developmental biology; Systems biology; Synthetic biology | ||||||
Degree Grantor: | California Institute of Technology | ||||||
Division: | Biology and Biological Engineering | ||||||
Major Option: | Biology | ||||||
Thesis Availability: | Public (worldwide access) | ||||||
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Defense Date: | 14 June 2022 | ||||||
Non-Caltech Author Email: | zhuronghui2011 (AT) gmail.com | ||||||
Record Number: | CaltechTHESIS:07252022-061122576 | ||||||
Persistent URL: | https://resolver.caltech.edu/CaltechTHESIS:07252022-061122576 | ||||||
DOI: | 10.7907/p0fn-qa56 | ||||||
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Default Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||
ID Code: | 14986 | ||||||
Collection: | CaltechTHESIS | ||||||
Deposited By: | Ronghui Zhu | ||||||
Deposited On: | 29 Jul 2022 18:37 | ||||||
Last Modified: | 02 Feb 2023 16:31 |
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