Modeling of subcellular signaling crosstalk in failing myocytes

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PROJECT SUMMARY/ABSTRACT. Heart failure (HF) is a rapidly growing health problem characterized by alterations in myocyte ion currents, Ca handling, contractile function and their neurohormonal regulation. Na dysregulation in HF is increasingly appreciated as a major, yet understudied aspect of cardiac function, linked to abnormal contraction, metabolic imbalance, and arrhythmia. By combining experimental and computational studies, this project aims to analyze quantitatively the contribution of various Na fluxes to the Na derangements in HF, and to link mechanistically intracellular Na dysregulation to mitochondrial function and cellular arrhythmias. Quantitative systems models that integrate across interacting biochemical and biophysical functions are essential for a mechanistic understanding of a complex clinical syndrome such HF, which involves multiple interacting systems. Here, we will develop the first integrative rabbit ventricular modeling framework including descriptions of intracellular Na and Ca handling, biochemically detailed models of Ca/calmodulin-dependent protein kinase II (CaMKII) and β-adrenergic signaling pathways, pH regulation, and mitochondrial function. The latter will be based on experimental data characterizing mitochondrial Ca handling and production of reactive oxygen species (ROS) in rabbit ventricular myocytes. The comprehensive model will be validated against a broad set of experimental data, and used to investigate how Na, Ca, CaMKII, ROS, and β-adrenergic signaling pathways contribute to (1) ionic remodeling in HF, (2) arrhythmia generation at the cellular level, and (3) metabolic imbalance. We will also test therapeutic approaches that target Na-related arrhythmias by specific inhibition of late Na current, CaMKII or ROS. Our study will provide enhanced mathematical models of these systems and substantially inform the development of pharmacological strategies. Moreover, the proposed project will significantly contribute to the personal and professional growth of the applicant. The first phase will provide an invaluable training opportunity, which will enhance the applicant’s competitiveness for faculty positions. Indeed, the proposed research plan will allow for acquisition of a broad interdisciplinary background in cardiac physio-pathology, refinement of computational skills, and training in new experimental techniques (i.e., cell culture and transfection, and confocal microscopy experiments). Completion of this training, under the supervision of an established and highly multidisciplinary mentoring team, will allow the applicant to diversify research goals and methods from those of his mentors, laying the groundwork for the development of future independent research projects and proposals. Continuation of the support during the second phase of the project will ensure the kick- off of the applicant’s independent academic career.