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Molecular Biology

Molecular Genetics: We are a worldwide referral center for research on patients with genetic pain disorders. Over the past two decades, we have built unique know-how and expertise in identifying and characterizing mutations in genes encoding voltage-gated sodium channels in patients with pain disorders. At the intake end, our staff has extensive expertise in assessing patients for inclusion in our studies, and in detailed phenotypic screening for genomic analysis.

Molecular Biology: Functional assessment is a key requirement for establishing pathogenicity of mutations in voltage-gated sodium channels and their interacting partners, especially in singleton cases where Mendelian inheritance is not discernible. This process necessitates designing and producing molecular tools, e.g., expression plasmids and stable cell lines, required for electrophysiological analysis (voltage-clamp, current-clamp, dynamic-clamp, multi-electrode arrays) and calcium-based imaging. The molecular biology of sodium channels channels is complicated due to the highly recombinogenic nature of constructs. We have developed protocols and expertise that ensure predictable and timely production of these tools. Our staff is highly experienced, and we validate our constructs at each stage of a project to insure fidelity. Our toolbox for functional genomics, including unique collections of DNA constructs, primers, and probes, is comprehensive and unique.

Molecular Modeling: Atomic-level structural modeling of voltage-gated sodium channels channels now provides more robust predictability due to the availability of crystal structures of bacterial voltage-gated sodium channels channels and cryo-EM structures of eukaryotic sodium channels, and improvements in computational algorithms. We have built the capability to use atomic-level structural modeling of mutant sodium channels, an approach that has revealed a structural basis for altered gating properties of these channels, and is essential for our genomically guided approach to precision pharmacotherapy.