? DESCRIPTION (provided by applicant): Nav channels figure crucially in cardiac and skeletal muscle. It is fitting then that channelopathic mutations throughout Nav1.5 (cardiac) and Nav1.4 (skeletal) channels, particularly in their carboxy tails (CTs), give rise to numerous arrhythmias and myotonias. Exploring such channelopathic disease will likely provide a clearer path towards understanding and developing new treatments for acquired arrhythmias of widespread prevalence. However, the actual changes in channel function and structure that result in even these channelopathic forms of disease have lacked a general understanding and deep foundational theory. Here, just published discoveries from our labs suggest a potentially transformational hypothesis that many of these channelopathic mutations act by weakening the binding of Ca2+-free calmodulin (apoCaM) to Nav channels, and that the absence of apoCaM on channels induces altered gating that directly accounts for the electrophysiological substrates underlying Brugada and long QT syndromes. Moreover, we have recently published the first atomic structure of apoCaM alone complexed with the CT of Nav1.5, allowing apoCaM modulation of Nav channel to be explored from an unprecedented structural perspective. Accordingly, we propose to combine single molecule functional analysis of Na channels, atomic structure of Na channels, and state-of-the-art cardiac disease models to understand and ultimately treat a broad class of Na channelopathic disease. In particular, this schema points naturally to new proof-of-principle therapeutic directions that will be investigated in this proposl. Overall, this genuinely multidisciplinary proposal, hosted by a seasoned and synergistic team, promise mechanistically deep advances towards understanding and treating forms of Brugada and long QT syndromes, and perhaps their related maladies of more general prevalence.
|Effective start/end date||4/1/16 → 3/31/17|
- National Heart, Lung, and Blood Institute: $1,072,747.00
- Cardiology and Cardiovascular Medicine
- Molecular Medicine
- Structural Biology