Mutation-Specific Calcium Dysregulation in Hypertrophic Cardiomyopathy
AdvisorTardiff, Jil C.
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PublisherThe University of Arizona.
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AbstractAs the genetic causes of Hypertrophic Cardiomyopathy (HCM) have become widely recognized, considerable lag in the development of targeted therapeutics has limited interventions to symptom palliation. This is in part due to an oft-noted finding that similar point mutations within myofilament proteins are known to cause differential disease severity, highlighting the need to understand disease progression at the molecular level. One commonly described pathway in HCM progression is calcium homeostasis dysregulation, albeit little is understood about disruption of the pathway. This dissertation investigated the calcium homeostasis of two clinically relevant murine models of HCM expressing similar point mutations within myofilament proteins. A mutation-specific alteration in the calcium dissociation rate from the cardiac myofilament is proposed to as a primary mechanism of down-stream calcium disruption. Two modes of intervention in down-stream calcium homeostasis were tested to as a means of improving directed therapies in HCM progression. The clinically-utilized diltiazem hydrochloride, an L-type calcium channel blocker, revealed mutation-specific symptom palliation but an inability to target within the disease mechanism itself. Due to this insufficient response to diltiazem, we investigated the role of the calcium-dependent kinase, CaMKII, and its persistent (autonomous) activation resulting from calcium dysregulation. Partial inhibition of the autonomous activation of the kinase was shown to improve functional and morphological indices of failure in calcium-dependent HCM progression. Thus, we conclude a myofilament-linked derangement in calcium homeostasis that potentiates aberrant activation of CaMKII. Moreover, we position the kinase as a nodal point in disease progression and a potential therapeutic target for early, robust management of HCM in the clinical population.
Degree ProgramGraduate College