We are grateful to the Office of Naval Research, the Army Research Office, the National Science Foundation, the Human Frontiers Science Program, the Department of Energy, the Stanley Center for Psychiatric Research, and the National Institutes of Health for financial support.
Structural DNA Nanotechnology
Synthetic nucleic acids can now be programmed to self-assemble with high structural fidelity using Watson-Crick base-pairing. This synthetic structural biological approach offers unprecedented control over the 3D architecture and chemical composition of large-scale macromolecular assemblies that can also be interfaced with natural and synthetic molecules inside and outside of the cell. Here, we are developing strategies to enable high-throughput and high fidelity design and synthesis of structured DNA and RNA assemblies for nanoscale imaging, therapeutic delivery, vaccines, and memory storage.
Programmed Nanoscale Energy Transport
Natural photosynthetic complexes consist of highly structured geometric assemblies of chlorophyll molecules that facilitate photon adsorption and energy transfer for the production of chemical fuel. Programmed self-assembly of DNA into precise 3D architectures can now be used to organize synthetic chromophores to replicate key aspects of bacterial photosynthetic systems. In this work, we are using structure-based design algorithms to program novel energy harvesting and transfer complexes using scaffolded DNA origami. We additionally synthesize these DNA-chromophore assemblies to test their programmed function to feedback to their rational structure-based design.
Multiplexed Imaging of Neuronal Synapse Proteins and RNAs
Neuronal synapses consist of hundreds of proteins organized at the sub-micron scale that facilitate synapse plasticity and signal transmission in normal brain development and function. While genetic studies have revealed numerous variations in neuronal synapse proteins that are associated with psychiatric and neurodegenerative diseases, it is unclear how these genetic variations impact neuronal synapse structure and function. In this research area we are applying synthetic nucleic acids to enable highly multiplexed imaging of synaptic proteins and their transcripts to resolve their sub-cellular localization, expression levels, and molecular associations. This research area aims to characterize the impact of genetic variation on neuronal synapse structure and function in intact tissues and cultures.
Signaling Localization and Cell Shape Analysis in Migration
Cell migration is a critical process in development, wound healing, and immune response, and its pathophysiological dysregulation is a fundamental hallmark of cancer metastasis. A systems-level characterization of how cells process external cues to initiate local activation of signaling cascades that lead to particular cell shapes and motility responses will enhance our understanding of mechanisms that govern cell migration. In this work we are applying live-cell imaging and cell shape analysis to characterize dynamical aspects of cell migration that integrate measurements of spatial and temporal features of signaling pathway activities, cell shape, and migratory response under the influence of physiologically-relevant extracellular perturbations. Models of this process seek to fill two fundamental gaps within the cell migration research field: the low-throughput nature of live cell imaging used to quantify cell motility, and the limited understanding of how molecular components of signaling pathways collectively orchestrate spatiotemporal polarization in cell shape during early stages of migration.
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