Individuals with chronic conditions such as heart disease and diabetes show impaired glucose and fatty acid oxidation and diminished energetic states in various tissue/organ systems. This is due to alterations in the signaling, biochemical, and structural components of metabolic pathways [63-69]. For example, remodeling in failing hearts results in impaired ability to oxidize both fatty acids and glucose [66], due to a down regulation of enzymes involved in poxidation [70, 71] along with an impaired ability to utilize glucose due to suppression of glycolytic activity and decreased ability of the cardiomyocytes to take up glucose [72]. In the extreme, the work capacity of the heart is limited not by the availability of substrates or O2, but by the impaired ability to consume the available substrates [65]. As H. Taegtmeyer has put it, """"""""...the heart fails in the midst of plenty"""""""" [73]. The goal of this scientific project is to understand the interactions among the transport and metabolic processes comprising energy metabolism at various biological scales (transporters/enzymes, mitochondria, cells, tissues/organs, whole-organism) in healthy and complex disease states. Specifically, models will account for the transport and metabolic characteristics of 5 rat strains identified in Section 1.3. The phenotypes associated with these strains are system properties that influence and are influenced by the metabolic state. Thus the metabolic modeling component of the VPR will be crucial to simulating complex traits associated with these strains. To test the robustness of the integrated metabolic model, the model will be used to simulate and predict physiological responses (e.g., substrate utilization and switching) to acetyl-CoA carboxylase 2 knock-out (ACC2(-/-)) which will be compared to measured physiological phenotypes. Since the metabolic inputs and outputs of all organs are coupled by transport through the cardiovascular system (CVS), the whole-body energy metabolism and solute transport models must be ultimately be coupled to the CVS models of Project 1.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM094503-02
Application #
8379057
Study Section
Special Emphasis Panel (ZGM1-CBCB-2)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$415,678
Indirect Cost
$96,509
Name
Medical College of Wisconsin
Department
Type
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Williams, Nakeya D; Mehlsen, Jesper; Tran, Hien T et al. (2018) An optimal control approach for blood pressure regulation during head-up tilt. Biol Cybern :
Olsen, Christian Haargaard; Ottesen, Johnny T; Smith, Ralph C et al. (2018) Parameter subset selection techniques for problems in mathematical biology. Biol Cybern :
Wright, Peter T; Bhogal, Navneet K; Diakonov, Ivan et al. (2018) Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in ?2AR-cAMP Responsiveness in Murine Hearts. Cell Rep 23:459-469
Ciocanel, Maria-Veronica; Docken, Steffen S; Gasper, Rebecca E et al. (2018) Cardiovascular regulation in response to multiple hemorrhages: analysis and parameter estimation. Biol Cybern :
Qureshi, M Umar; Colebank, Mitchel J; Schreier, David A et al. (2018) Characteristic impedance: frequency or time domain approach? Physiol Meas 39:014004
Herum, Kate M; Choppe, Jonas; Kumar, Aditya et al. (2017) Mechanical regulation of cardiac fibroblast profibrotic phenotypes. Mol Biol Cell 28:1871-1882
McClymont, Darryl; Teh, Irvin; Carruth, Eric et al. (2017) Evaluation of non-Gaussian diffusion in cardiac MRI. Magn Reson Med 78:1174-1186
Sturdy, Jacob; Ottesen, Johnny T; Olufsen, Mette S (2017) Modeling the differentiation of A- and C-type baroreceptor firing patterns. J Comput Neurosci 42:11-30
Tewari, Shivendra G; Bugenhagen, Scott M; Palmer, Bradley M et al. (2016) Dynamics of cross-bridge cycling, ATP hydrolysis, force generation, and deformation in cardiac muscle. J Mol Cell Cardiol 96:11-25
Tewari, Shivendra G; Bugenhagen, Scott M; Vinnakota, Kalyan C et al. (2016) Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure. J Mol Cell Cardiol 94:162-175

Showing the most recent 10 out of 116 publications