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James D. Fessenden, PhD
Scientist, Brigham and Women's Hospital
Assistant Professor of Anaesthesia, Harvard Medical School

Brigham and Women's Hospital
Department of Anesthesiology, Perioperative and Pain Medicine
75 Francis Street
Boston, MA 02115

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Research Narrative:

In the Fessenden Lab, we use innovative fluorescence microscopic techniques to examine the fine structure of the ryanodine receptor, an enormous intracellular Ca2+ channel that plays an integral role in excitation contraction (EC) coupling in both cardiac and skeletal muscle.  The ryanodine receptor is the largest ion channel known and though its function has been well-established, knowledge of its structure has proved elusive.  A central question in the field of EC coupling is how single amino acid point mutations in the ryanodine receptor, which is over 5000 amino acids long, can lead to diverse muscle disorders including malignant hyperthermia, central core disease, cardiac arrhythmias and sudden cardiac death.  We have undertaken a structural biological approach to this problem by mapping the ryanodine receptor using fluorescence resonance energy transfer (FRET), a technique that allows us to measure physical distances on the protein itself. We perform these measurements by directing fluorescent molecules to specific sites on the ryanodine receptor and then measuring energy transfer between them.  The FRET data we generate enables us to identify these specific sites within the large cryo EM “map” of the protein, which depicts its overall shape.  Our long-term goal is to use our mapping techniques to determine how single amino acid mutations perturb ryanodine receptor structure, in order to gain insights into how these mutations lead to muscle disease.  Ultimately, we would like to use our FRET-based assays to identify molecules that can reverse structural lesions caused by these single amino acid mutations and thereby might eventually be used in therapeutic treatments to reverse these debilitating muscle disorders.