Team:SUSTech Shenzhen/Description
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Inspiration and Project Description
Inspiration
Our initial project inspiration comes from a tough therapeutic situation: Cytokine Release Syndrome in cancer immunotherapy. Cytokines is a large and loosely defined family of small proteins, secreted by immune cells, endothelial cells, and stromal cells. [1] They are immunomodulating agents which interact with cell surface receptors, and induce autocrine, paracrine and endocrine signaling. They are extensively studied in the laboratory for their potential roles in medical applications. For example, cancer immunotherapy becomes the latest hope for cancer treatment. It utilizes cytokines or antibodies, or genetically programed immune cell that produces them (such as Car-T) to recognize specific cancer cells and modulate patients’own immune responses. Currently, the main limitation of these therapy is the absence of accurately controlled production level of target protein. Failure of the precise control often lead to fetal side effects such as CRS (cytokine release syndrome), and limited therapeutic efficacy.[2] The comic below shows our understanding of injected immune cell behaviors in cancer immnotherapy.
To effectively manipulate the desired cell behavior, we realized that an important fundamental question needs to be solved, which is to carry out the modelling between a specific protein level such as cytokine and corresponding cellular response. In order to carry out such study, we need to be able to spatiotemporal control of the level of cytokine understudied. However, it is difficult to achieve it in mammalian cell due to their complex multi-level regulation mechanisms involved, such as transcription, translational regulations, and mRNA/ protein process, modification, transportation and degradation. In our project, we introduced “C-hoop”, an integrated framework to accurately understand this complicated process and attempt to quantitatively manipulation of specific desired behavior in HeLa cell line.
Description
We addressed three essential objectives to construct the “C-hoop” method. First of all, we effectively modulate the input(transcription), obtain corresponding output at different scales, which we named it" multi-level output strategy". To this end, we transfected into HeLa cell a light-switchable transcriptional factor "LightON" (2012, X.Wang et al)[3] to control cytokine gene expression and obtained multi-level output data such as transcription, protein secretion and cell metabolic condition. Secondly, we eliminated the well-to-well variation by construction of AICCS, an automatic illumination and regular collection of secreted proteins. Thirdly, we designed a Model-based predictive and control system for achieving desired dynamic range of output protein expression and wrote an algorithm to analyze the immune cell immigration triggered by the output of our system.
References
- ↑ Mubeccel Akdis, Reto Crameri and Cezmi A. Akdis. (2016). Interleukins (from IL-1 to IL-38), interferons, transforming growth factor b, and TNF-a: Receptors, functions, and roles in diseases. Fundamentals of allergy and immunology
- ↑ Ling Zhang, Sid P Kerkar, Zhiya Yu, Zhili Zheng, Shicheng Yang, Nicholas P Restifo, Steven A Rosenberg, Richard A Morgan, Improving Adoptive T Cell Therapy by Targeting and Controlling IL-12 Expression to the Tumor Environment, Molecular Therapy
- ↑ Wang, X. , Chen, X. , & Yang, Y. . (2012). Spatiotemporal control of gene expression by a light-switchable transgene system. Nature Methods, 9(3), 266-269.