Nanocytometry Core will support the efforts of the Chicago Region-PSOC to determine how factors modulating the spatio-temporal organization of chromatin impact gene expression in cancer by providing quantitative analysis of the physical structure of chromatin with nanoscale sensitivity and super-resolution imaging. All three projects of the CR-PSOC require the capability to quantitate alterations in higher-order and large-scale chromatin structure to meet their specific aims. The goal for the Nanocytometry Core is to provide this resource. Higher-order/large-scale chromatin structure plays a critical role in gene regulation, and its dysregulation is a hallmark of most cancers. This involves a hierarchy of length scales from a few tens of nanometers for nucleosomes to hundreds of nanometers for chromatin loops. Prior studies have been stymied by a lack of robust and quantitative experimental techniques to study these small length scales. We will develop a unique instrumentation resource to address this need. The new instrument will combine two complementary micro/nanoscopic techniques: partial wave spectroscopic (PWS) nanocytometry, recently developed by members of CR-PSOC, which quantifies the statistical properties of molecular density distribution within live or fixed cells for length scales from 10 to 200 nm, and Stochastic Optical Reconstruction Microscope (STORM), a super-resolution microscopy offering molecular-specific images with resolution as high as ~20-60 nm. The Core will develop a combined STORM-nanocytology system allowing for seamless integration of the two microscopy techniques with a co-registration capability. The nanocytometry module will be improved beyond the state-of-the-art by substantially increasing its speed (milliseconds) for live cell imaging. This will be a unique instrument that does not exist anywhere else in the world. It will allow imaging and sensing of chromatin structure with sensitivity down to 10-20 nm in live as well as fixed cells, and can work with individual cells as well as able to analyze thousands of cells across an entire slide within minutes. The system will will open up new directions for basic science as well as translational research. The Core will maintain the infrastructure, including highly-trained and permanent engineering staff, as necessary for the support of the CR-PSOC projects, which will have priority access to the resource. Because the capabilities of the Core are so unique and may cut across not only the CR-PSOC but also other PSOCs, we anticipate that it will be of use to other projects within the PSO Network.
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