This is a revised application in response to PAR-11-203: Predictive Multiscale Models for Biomedical, Biological, Behavioral, Environmental and Clinical Research (Interagency U01). Analyzing the Cardiac Power Grid: Adaptive responses to fluctuating local demand brings together seasoned investigators at U Washington, UC San Diego, University of Michigan, and Medical College of Wisconsin. This project will provide a central, core structure for integrative thermodynamically- and anatomically-constrained versions of the Cardiac Physiome, a large multiscale, multi-modular computer representation and resource for collating, coalescing and conciliating models as hypotheses and data from all 4 groups as tests of their validity. The research products will be publicly available, comprehensive data and models systematizing these data from subcellular, cell, tissue and organ levels: these will guide further experimental studies to test hypotheses and to identify therapeutic targets. The models will be composed of reproducible modules, each modifiable to accommodate new knowledge, and each in several forms ranging from simple descriptive to deeply mechanistic. The approach is middle out, neither top-down, nor bottom-up, but cell-centric, covering interactions among several cell types, with information flow up to the organ level and down to the protein level, so providing the sites for future linkages to regulate transcription. The data, he tools developed, the modules and the composite models, and the reproducible exchange packages (REP) of data and models are all open source. The three aims span Cell, Tissue, and Organ levels, and are strongly intertwined:
(Aim 1) Power Generation and its Distribution on the Grid focuses on cellular and mitochondrial energetics, substrates for energy supply and purine nucleoside transport and exchange. It is given the largest write-up and is used as the power source by Aims 2 and 3.
(Aim 2) Heterogeneities in Power Dissipation: Local Workloads links anatomic (high-resolution ventricular fiber and sheet arrangements), physiologic (excitatory spread and force generation) and metabolic (ATP and substrate use) to relate to regional myocardial blood flows.
(Aim 3) Cardiomyocyte Control of Flows of Substrates for Power Generation involves 4 cell types (cardiomyocyte, smooth muscle, endothelium and RBC) and the relationships amongst them controlling blood flow.
(Aim 4) Simulation Resource Core provides tools for modeling analysis of data, develops new technology for the semi-automated assembly, and disassembly and modification of models using reusable modules. Annotation of model code against standard ontologies identifies model elements precisely, and facilitates reuse by researchers worldwide.

Public Health Relevance

This project will provide a central, core structure of our integrative, thermodynamically constrained version of the Cardiac Physiome, a large multiscale, multi-modular computer representation and a resource for collating and coalescing models as hypotheses and data serving as tests of the models' validity. The four-university consortium will perform lab studies and will make publicly available models of cardiac metabolism, excitation, contraction, and regional blood flows conciliating diverse sets of data (theirs and others') into a self-consistent integrated whole in order to guide selection of future experiments and to identify therapeutic targets, for example in myopathies and cardiac failure. Long range goals are to provide a framework for incorporating the protein-protein network connectivities in the regulation of the cardiac transcriptome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL122199-01A1
Application #
8797154
Study Section
Special Emphasis Panel (ZEB1-OSR-C (O1))
Program Officer
Lee, Albert
Project Start
2015-09-15
Project End
2020-05-30
Budget Start
2015-09-15
Budget End
2016-05-30
Support Year
1
Fiscal Year
2015
Total Cost
$706,034
Indirect Cost
$172,842
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Li, Tao; Zhang, Zhen; Kolwicz Jr, Stephen C et al. (2017) Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. Cell Metab 25:374-385
Tan, Philip M; Buchholz, Kyle S; Omens, Jeffrey H et al. (2017) Predictive model identifies key network regulators of cardiomyocyte mechano-signaling. PLoS Comput Biol 13:e1005854
Dewan, Sukriti; McCabe, Kimberly J; Regnier, Michael et al. (2017) Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants-Genotype to Cellular Phenotype. Front Physiol 8:151
Herum, Kate M; Lunde, Ida G; McCulloch, Andrew D et al. (2017) The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart. J Clin Med 6:
Dewan, Sukriti; Krishnamurthy, Adarsh; Kole, Devleena et al. (2017) Model of Human Fetal Growth in Hypoplastic Left Heart Syndrome: Reduced Ventricular Growth Due to Decreased Ventricular Filling and Altered Shape. Front Pediatr 5:25
Teichman, Sam L; Thomson, Kassandra S; Regnier, Michael (2017) Cardiac Myosin Activation with Gene Therapy Produces Sustained Inotropic Effects and May Treat Heart Failure with Reduced Ejection Fraction. Handb Exp Pharmacol 243:447-464
Herum, Kate M; Choppe, Jonas; Kumar, Aditya et al. (2017) Mechanical regulation of cardiac fibroblast profibrotic phenotypes. Mol Biol Cell 28:1871-1882
Pannala, Venkat R; Camara, Amadou K S; Dash, Ranjan K (2016) Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition. J Appl Physiol (1985) 121:1196-1207
Cheng, Yuanhua; Lindert, Steffen; Oxenford, Lucas et al. (2016) Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation. J Phys Chem B 120:8238-53
Blomeyer, Christoph A; Bazil, Jason N; Stowe, David F et al. (2016) Mg(2+) differentially regulates two modes of mitochondrial Ca(2+) uptake in isolated cardiac mitochondria: implications for mitochondrial Ca(2+) sequestration. J Bioenerg Biomembr 48:175-88

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