BME: DNA Origami for Investigating and Reprogramming Cell Signaling

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PI: LaBean, Thom Proposal Number: 1603179Complex webs of cell signaling pathways make up cell-to-cell communication networks responsible for everything from homeostasis (maintaining equilibrium within our body), to wound healing, to development, and to immunity. These communication systems make use of direct contact between neighboring cells through specific nanometer-scale organization and presentation of cell surface receptors and ligands. This project will use a unique molecular engineering tool, termed DNA origami (or DNA folding), to determine how genes that control the production of proteins on the outer membranes of cells (major histocompatibility complex or MHC) interact with T-cell receptors (TCR). The interaction of the MHC and the TCR is the first step in the T-cell activation process, which impacts important biomedical issues in normal immune function, cancer, and autoimmune disease. Thus, the work in this proposal has the potential to enable a powerful toolkit for performing fundamental biological studies on receptor dynamics and developing therapies for immunological disorders. The goal of this project is to employ the rich palette of molecular engineering tools provided by structural DNA nanotechnology to specifically organize, orient, and present biologically active molecules to living cells in order to understand, facilitate, interrupt, and reprogram molecular interactions involved in cell signaling. Complex webs of cell signaling pathways make up the cell-to-cell communication networks responsible for everything from homeostasis, to wound healing, to development, and to immunity. These communication systems often make use of direct contact between neighboring cells via specific nanometer-scale organization and presentation of cell surface receptors and ligands they interact with. Specifically, the project will examine the spacing and multiplicity of presentation of the major histocompatibility complex (MHC) and its interaction with T-cell receptors (TCR) on the surfaces of living cells. The interaction of MHC and TCR is the first step in the complex biochemical cascade involving T-cell activation that impacts important biomedical issues in normal immune function, cancer, and autoimmune disease. DNA origami, a subset of DNA nanotechnology, will be assembled with designed architectures, patterns, and structural reinforcement in order to test a range of hypotheses in cell signaling science that would be very difficult or impossible to test by other, less programmable experimental methods. Novel basic science can now be pursued as well as testing of possible therapeutic strategies using DNA origami molecular assemblies displaying proteins, ligands, receptors, aptamers, small molecules, and other cell effectors. The combination of well-engineered experimental set-ups for probing individual cell-cell interactions allied with the programmable molecular recognition platforms of DNA-based nanostructures represents a new intellectual frontier with significant long-term potential in understanding biology and affecting human health. The program will lead to development of naturally biocompatible molecular organizers for a variety of biological and biomedical applications. Results from this study may provide major advances in understanding important events in T-cell activation and in cell-to-cell communications in general. Future extensions of this project could involve application of molecular materials and methods developed here toward other cell signaling pathways critical to understanding and improving human health. Graduate students will gain valuable opportunities for education and research training. The PI has consistently involved undergraduate, high school, and under-represented students in research programs and will redouble efforts to do so on this project