OF WORK As a result of extensive collaboration with Clara Franzini-Armstrong we have obtained extensive statistical data on the distribution of organelles and ryanodine receptors in rabbit siono-atrial node cells. These data indicated that the parameters of our 3D stochastic SANC model need to be extensively revised. However, paradoxically, when the new geometry is inserted in thhe model, the results no longerr agree with experiment. To resolve this paradox we have done extensive imaging using ultra-resolution SIM micrroscopy, and have developed software that enables 3D reconstruction of the location and size of ryanodine receptor clusters, which will be used directly in the model. We have developed software that an detect, classify and track calcium release event in 3D+time, both in simulations and in experimental records. This has led to new understanding of the way that propagation occurs in the model as a function of adrenergic stimulation, and to the discovery that there are many more release events in experimental records than previously suspected. We have begun studies of heterogeneity of cells within the sinus node, both in isolated cells and in high space and time resolution images of whole sinus node preparations from mouse. This has led to the hypothesis that some pacemaker cells may be quiescent at rest and be recruited under conditions of adrenergic (fight-or-flight) stimulation. We have recently initiated a collaboration with George Washington University to isolate human sino-atrial node cells, which is uncharted territory and we hope will lead to the ability to model diseases of heart-rate regulation such as sick-sinus syndrome, as well as shed light on the mechanism of decline of heart rate reserve with aging. As advised by the Board of Scientific Counselors, we are undertaking to translate our extensive modeling software into a form that can be used by other investigators.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000844-20
Application #
9351974
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Kim, Mary S; Maltsev, Alexander V; Monfredi, Oliver et al. (2018) Heterogeneity of calcium clock functions in dormant, dysrhythmically and rhythmically firing single pacemaker cells isolated from SA node. Cell Calcium 74:168-179
Monfredi, Oliver; Tsutsui, Kenta; Ziman, Bruce et al. (2018) Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell. Am J Physiol Heart Circ Physiol 314:H403-H414
Tsutsui, Kenta; Monfredi, Oliver J; Sirenko-Tagirova, Syevda G et al. (2018) A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells. Sci Signal 11:
Maltsev, Anna V; Maltsev, Victor A; Stern, Michael D (2017) Clusters of calcium release channels harness the Ising phase transition to confine their elementary intracellular signals. Proc Natl Acad Sci U S A 114:7525-7530
Maltsev, Alexander V; Parsons, Sean P; Kim, Mary S et al. (2017) Computer algorithms for automated detection and analysis of local Ca2+ releases in spontaneously beating cardiac pacemaker cells. PLoS One 12:e0179419
Maltsev, Alexander V; Maltsev, Victor A; Stern, Michael D (2017) Stabilization of diastolic calcium signal via calcium pump regulation of complex local calcium releases and transient decay in a computational model of cardiac pacemaker cell with individual release channels. PLoS Comput Biol 13:e1005675
Alexander-Shani, Rivka; Mreisat, Ahmad; Smeir, Elia et al. (2017) Long-term HIF-1? transcriptional activation is essential for heat-acclimation-mediated cross tolerance: mitochondrial target genes. Am J Physiol Regul Integr Comp Physiol 312:R753-R762
Stern, Michael D; Maltseva, Larissa A; Juhaszova, Magdalena et al. (2014) Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells. J Gen Physiol 143:577-604
Maltsev, Victor A; Yaniv, Yael; Maltsev, Anna V et al. (2014) Modern perspectives on numerical modeling of cardiac pacemaker cell. J Pharmacol Sci 125:6-38
Stern, Michael D; RĂ­os, Eduardo; Maltsev, Victor A (2013) Life and death of a cardiac calcium spark. J Gen Physiol 142:257-74

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