Whether due to mutations in genes or environmental factors, cancers are defined by unregulated cell growth. This abnormal cell growth has the potential to spread throughout the body, disrupting vital processes. Developing new treatments and diagnostics requires a deep understanding of the molecular interactions and structures within cancerous cells, and how they differ from corresponding healthy cells. Optical microscopes are limited to resolutions of about 0.2 microns, whereas with transmission electron microscopy, 1000x higher resolutions are possible. At such resolutions the 3-D structures extending down to individual molecules within the cell become resolved. This technique can also be u...

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Whether due to mutations in genes or environmental factors, cancers are defined by unregulated cell growth. This abnormal cell growth has the potential to spread throughout the body, disrupting vital processes. Developing new treatments and diagnostics requires a deep understanding of the molecular interactions and structures within cancerous cells, and how they differ from corresponding healthy cells. Optical microscopes are limited to resolutions of about 0.2 microns, whereas with transmission electron microscopy, 1000x higher resolutions are possible. At such resolutions the 3-D structures extending down to individual molecules within the cell become resolved. This technique can also be used to study the 3-D structures of individual molecular assemblies to near-atomic resolution. This proposal will add new technologies to the two CryoEM Cores in the Texas Medical Center (TMC), and will provide these technologies to all cancer researchers in other TMC and surrounding area Institutions. First, we will purchase a Thermo Fisher Talos Arctica, the companion instrument to the Krios microscope already installed at UTHealth that is required for a complete CyroEM research pipeline. The Arctica instrument will also provide several new capabilities including MicroED, a new technique for solving high resolution structures of macromolecules using crystals a fraction of a micron in size. This method can be used for drug development, to study how drugs bind to their protein targets and develop improved drugs based on how they interact. Second, we will purchase a Thermo Fisher Aquilos Cryo-FIB, an instrument which can precisely cut 200 nm slices from the middle of rapidly frozen cells, so they can be imaged in 3-D on the Arctica or Krios. This imaging can provide 3-D cellular structure at molecular resolution, allowing researchers to visualize how cancer impacts the molecular interactions within the living cell.

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