Research Summary

Calcium Signaling

Dr. Jafri's early career focused on computational modeling to address fundamental questions about agonist-induced calcium signaling. In these studies, he demonstrated mechanisms of calcium oscillations waves suggesting a regime of calcium wave behavior that had not previously been considered. He further demonstrated the roles of exogenous and endogenous buffers on shaping calcium oscillation and wave dynamics suggesting critical limits on the amount of exogenous buffer that could be added before perturbing the native behavior. These predictions were late verified by experiments by other groups. He has also shown how calcium signaling can impact downstream processes such as transcription factor activation in T lymphocytes.
  • Jafri, M. S. and J. Keizer. 1994. Diffusion of IP3, but not Ca2+, is necessary for a class of IP3-induced Ca2+ wave trains. Proc. Natl. Acad. Sci. USA 91:9485-9489. PMID: 7937794. PMCID: PMC44837
  • Jafri, M. S. and J. Keizer. 1995. On the roles of Ca2+ diffusion, Ca2+ buffering, and the endoplasmic reticulum in IP3 induced Ca2+ release. Biophys. J. 69:2139-2153. PMID: 8580358. PMCID: PMC1236448
  • Jafri, M. S. and J. Keizer. 1997. Agonist-induced calcium waves in oscillatory cells: a biological example of Burgers' equation. Bull. Math. Biol. 59:1125-1144. PMID: 9358737
  • W. G. Fisher, P.-C. Yang, R. K. Medikonduri, and M. S. Jafri. 2006. NFAT and NFκB Activation in T Lymphocytes: A Model of Differential Activation of Gene Expression. Ann. Biomed. Eng. 34(11):1712-28. PMID: 17031595. PMCID: PMC1764593

    • Cardiac Excitaiton-Contraction Coupling

    Dr. Jafri’s more recent scientific contributions are in the area of cardiac ventricular excitation-contraction coupling. The early studies involved deterministic models for the ventricular myocyte. These studies were the first to incorporate a dyadic subspace into ventricular myocyte models (rat, mouse, and guinea pig) and atrial myocytes (sheep) include biophysically detailed descriptions of calcium release and uptake. Most models of excitation-contraction coupling have adopted this approach. He also suggested the mechanisms by which the pacing rate can govern the amplitude and duration of the calcium transient (interval-force relations) and action potential. He also showed how gene expression changes during heart failure can lead to the heart failure phenotype. In these studies, a novel and significant role for calcium dynamics was suggested and later experimentally verified by others. He has also studied how stretch-activated mechanisms affect excitation-contraction coupling.
  • Jafri, M. S., J. J. Rice and R. L. Winslow. 1998. Cardiac calcium dynamics: the roles of ryanodine receptor adaptation and sarcoplasmic reticulum Ca2+ load. Biophys. J. 74:1149-1168. PMID: 9512016. PMCID: PMC1299466
  • Winslow, R. L., J. J. Rice, M. S. Jafri, E. Marban, and B. O'Rourke. 1999. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure II. model studies. Circ. Res. 84:571-586. PMID: 10082479
  • Wescott, A. P., M. S. Jafri, W. J. Lederer, and G. S. B. Williams. 2016. Ryanodine Receptor Sensitivity Governs the Stability and Synchrony of Local Calcium Release during Cardiac Excitation-Contraction Coupling. J Mol Cel Cardiol. 92:82-92. PMID: 26827896 PMCID: PMC4807626
  • Limbu S, T. M. Hoang-Trong, B. L. Prosser, W. J. Lederer, and M. S. Jafri. 2015. Modeling Local X-ROS and Calcium Signaling in Heart. Biophys. J. 109(10):2037-2050. PMID: 26588563 PMCID: PMC4656861

    • Calcium Sparks

    Realizing some of the limitation of deterministic common pool models for certain behaviors observed in cardiac ventricular myocytes, Dr. Jafri has also made significant contributions developing methods to study local control models for cardiac-excitation contraction coupling to overcome the high computational cost of stochastic local control simulations. In this regard, he worked on probability density and moment closure formulation that approximated the stochastic system using probability density functions improving computational efficiency if the systems can be simplified. To overcome the need for system simplification , e also developed the Ultra-fast Monte Carlo methods that combined with modern parallel architecture yield massive speed-up making stochastic simulation of cardiac tissue possible.
  • Sobie, E. A., K. W. Dilly, J. d. S. Cruz, W. J. Lederer, and M. S. Jafri. 2002. Termination of cardiac of Ca2+,sparks: an investigative mathematical model of Ca2+-induced Ca2+ release. Biophys. J. 83:59-78. PMID: 12080100. PMCID: PMC1302127
  • Williams, G. S., M. A. Huertas, E. A. Sobie, M. S. Jafri, and G. D. Smith. 2007. A probability density approach to modeling local control of calcium-induced calcium release in cardiac myocytes. Biophys. J. 92:2311-2328. PMID: 17237200. PMCID: PMC1864826
  • Williams, G. S., M. A. Huertas, E. A. Sobie, M. S. Jafri, and G. D. Smith. 2008. Moment closure for local control models of calcium-induced calcium release in cardiac myocytes. Biophys. J. 95(4):1689-1703. PMID: 1848729. PMCID: PMC2483752.
  • Jafri, M. S. and T. M. Hoang-Trong. Method and system for utilizing Markov Chain Monte Carlo simulations. U. S. Patent 9,009,095.

    • Novel Algorithms

    Dr. Jafri has a history of developing novel computing algorithms. For example, the advanced Ultra-fast Monte Carlo Method has enabled Dr. Jafri to suggest mechanisms for previously unknown scientific questions. For example, he has characterized that the calcium leak out of the sarcoplasmic can be completely accounted for by ryanodine receptor opening without invoking theoretical possibilities. He has shown how rearrangement of the microarchitecture of the cardiac myocyte impacts excitation-contraction coupling during heart failure and atrial fibrillation. He also has developed methods to predict the phenotype caused by genetic variants.
  • McCoy, M. D., V. Shivakumar, S. Nimmagadda, M. S. Jafri, and S. Madhavan. 2019. SNP2SIM: a modular workflow for standardizing molecular simulation and functional analysis of protein variants. BMC Bioinformatics 20:171-178.
  • G. S. Williams, A. C. Chikando, T. M. Hoang-Trong, E. A. Sobie, W. J. Lederer, and M. S. Jafri. 2011. Dynamics of Calcium Sparks and Calcium Leak in Heart. Biophys. J. 101:1287-1296. PMID: 21943409. PMCID: PMC3177068.
  • Macquaide, N., M. T. Hoang-Trong,J-I Hotta, W. Sempels, I. Lenaerts, P. Holemans, J. Hofkens, M. S. Jafri, R. Willems, and K. R. Sipido. 2015. Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation. Cardiovasc. Res. 108(3):387-398. PMID: 2649074 PMCID: PMC4648199
  • Wagner, E. M. Lauterbach, T. Kohl, G. S. Williams, J. H. Steinbrecher, J. H. Streich, B. Korf, H. T. Tuan, B. Hagen, S. Luther, G. Hasenfuss, U. Paritz, M. S. Jafri, S. W. Hell, W. J. Lederer, and S. E. Lehnart. 2012. STED live cell super-resolution imaging shows proliferative remodeling of t-tubule membrane structures after myocardial infarction. Circ. Res. 111(4):402-414

    • Mitochondrial Energy Metabolism

    Dr. Jafri has also made significant contributions in the area of mitochondrial energy metabolism and ionic homeostasis. Through his computational models he has demonstrated how ions such as calcium, sodium and protons are regulated and how the influence energy metabolism. Furthermore, these explorations suggest how different chemical species such as calcium, NADH, ATP, ADP, protons, and phosphate serve to stimulate energy production during exercise.
  • M-H. T. Nguyen and M. S. Jafri. 2005. Mitochondrial calcium signaling and energy metabolism. Ann. N. Y. Acad. Sci. 1047:127-137. PMID: 16093491
  • Jafri, M. S., and M. Kotulska. 2006. Modeling the Mechanism of Metabolic Oscillations in Ischemic Cardiac Myocytes. J. Theor. Biol. 242(4):801-817. PMID: 16814324
  • Nguyen, M. T., S. J. Dudycha, and M. S. Jafri. 2007. The effects of Ca2+ on cardiac mitochondrial energy production is modulated by Na+ and H+ dynamics. Am. J. Physiol. Cell Physiol. 292(6):C2004-2020. PMID: 17344315
  • Mannella, C. A., W. J. Lederer, and M. S. Jafri. 2013. The connection between inner membrane topology and mitochondrial function. J. Mol. Cell. Cardiol. 62C:51-57. PMID: 23672826 PMCID: PMC4219563

    • Complete List of Published Work in MyBibliography :

    Ongoing Research Support

    none

    Completed Research Support

    National Institutes of Health U01HL116321 05/01/2014-04/30/2019
    Title: Multiscale Spatiotemporal Modeling of Cardiac Mitochondria
    Role: PI
    Goals: The project integrates experiments and modeling spanning multiple scales to understand how mitochondrial cristae structure and the localization of proteins defines mitochondrial function and how these change during disease.

    National Institutes of Health R01HL105239 1/1/11-11/30/15
    Title: Calcium Entrained Arrhythmias
    Role: PI
    Goals: The project integrates experiments and multi-scale modeling to gain a systems level understanding of the molecular and cellular events that lead to cardiac arrhythmias that are due to a defect in cardiac calcium dynamics.

    National Institutes of Health R01AR057348 5/1/10-4/30/15
    Title: Pathogenesis and Pathophysiological Mechanisms of Myofascial Trigger Points
    Role: Co-PI
    Goals: The project studies the mechanisms behind myofascial trigger points. It also studies evaluation methods for diagnosis and treatment outcomes for trigger points and correlates this with biochemical and physiological measurements.

    National Science Foundation DMS – 0443843 3/15/05-2/24/11
    Title: Ensemble Density Analysis for Stochastic Models of Cardiac Excitation-Contraction Coupling
    Role: PI
    Goals: The project developed methods to study and model the stochastic calcium release units in cardiac excitation contraction coupling and use them to understand the basic mechanism of excitation-contraction coupling in normal and failing hearts.

    Saleet Jafri
    Tue Oct 6 11:34:52 EDT 2020