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Designing and Constructing a Set of Fundamental Cell Models: Application to Cardiac Disease James B.Bassingthwaighte University of Washington Seattle Silico.6.01 Engineering and reverse engineering the route from Genome to Function: (Integrating Biological Systems Knowledge) The Physiome Project http://www.physiome.org Tissue Cell Molecule Genes Organism Health Organ Structure and Function: • Biomedical Problem Formulation • Quantitative Approaches • Engineering Methods • Mechanistic System Modeling • Databasing & Dissemination Silico.6.01 The Physiome and the Physiome Project • The “Physiome”, like the Genome, is a quantitative description of the functional behavior of the physiological state of an individual of a species. In its fullest form it should define relationships from organism to genome and vice versa. • The “Physiome Project” is a concerted effort to define the Physiome through databasing and through the development of a sequence of model types: schema of interactions, descriptions of structure and function, logical prediction, and integrative quantitative modeling for critical projections. Silico.6.01 Physiome and Physiome Project • The models of genomic, metabolic, or integrative systems should, via iteration with carefully designed experiments, resolve contradictions amongst prior observations and interpretations. • Reasonably comprehensive and accurate models will demonstrate emergent properties. This is the “reverse engineering” of biology. Some of these will be applied to clinical diagnosis and the evaluation of care. • Databases, concepts, descriptions, and models are to be put in the public domain, an open system. Silico.6.01 Structure with Function • The Genome, and the Transcriptome. THE PHYSIOME: • The physico-chemical status. • Descriptions of the Proteome, of solutes, bilayers, organelles, organs, organisms. • Quantitative measures of structural components, e.g. protein and solute levels in cells and organelles, volumes, surface areas, material properties, etc. (The Morphome) • Schema of interactions between the components. Regulatory apparatus for gene expression and metabolism. (The Metabolome) • Computational models (genes +milieu organism). Silico.6.01 Three Incentives for Developing the Physiome • To develop understanding of a mechanism or a phenomenom: basic science. • To determine the most effective targets for therapy, either pharmaceutic or genomic. • To design artificial or tissue-engineered, biocompatible implants. Silico.6.01 An example: LBBB Left Bundle Branch Block of the Cardiac Conduction System Auscultation: Reverse splitting of the second heart sound ECG: Wide QRS complex and often late T wave X-ray: Moderate cardiac enlargement Thallium scan: Low flow in the septum PET scan: Decreased septal glucose uptake, but normal septal fatty acid uptake. The imaging gave three clues to the physiology. How can the observations be explained? Silico.6.01 Electrical activation of the normal heart sinus node left atrium His bundle AV node bundle branches right ventricle Purkinje fibers Prinzen et al., 2000 Silico.6.01 Schematics of electrical activation RV apex pacing left bundle branch block X Prinzen et al., 2000 Silico.6.01 Explaining what is observed in Left Bundle Branch Block ECG: Wide QRS complex and often late T wave The RBB is activated normally, and excitation proceeds normally over the RV, but since the left branch of the bundle of His is blocked the spread of activation into the left ventricular muscle is delayed 50 to 100 ms, broadening the QRS complex, and delaying the repolarization phase (late T wave) Silico.6.01 MRI tagging of Cardiac Contraction Pacing spike ECG ... Presat. pulse 50ms 90ms 130ms ... Gx RF Tagging pulse Delay = 50 ms Delay = 90 ms Delay = 130 ms (Prinzen, Hunter, Zerhouni,1999) Silico.6.01 Explaining what is observed in Left Bundle Branch Block Auscultation: Reversed splitting of S2 (second heart sound) The RBB is activated normally, but activation of the left ventricle is delayed 50 to 100 ms, so that aortic valve closing is delayed and is later than pulmonic closing, rather than earlier. During inspiration increased RV filling, delaying pulmonic valve closure, shortens (rather than lengthening) the interval between pulmonic and aortic valve closure: reversed respiratory influence on second sound splitting interval. Normally, Insp longer A2–P2 , but here Insp shorter P2–A2 Silico.6.01 Segment length Effect of RV apex pacing on regional LV epicardial fiber strain early-activated late-activated Prinzen et al, Am. J. Physiol, 1990 Silico.6.01 Distribution of external work in the LV wall Atrial pacing RV apex pacing LV free wall pacing . (mJ/g) 8 . . septum anterior * * posterior 00 Fiber length Fiber stress Fiber stress Fiber stress Prinzen et al, J Am Coll Cardiol, 1999 Fiber length Fiber length Silico.6.01 To explain what is seen in LBBB: Thallium scans: Decreased septal blood flow relative to rest of LV because local demand is reduced. Decreased septal mass due to local atrophy. PET Glucose Uptake: Decreased septal uptake due to shift away from glucose with diminished demand relative to supply. PET data show normal FA uptake. Regional FA uptake is matched to local flow. X-ray: LV hypertrophy: Hypertrophic free wall due to increased workload and low contractile efficiency. This is partially attributable to increased wall tension with LV cavity volume increase: T=PxR. Silico.6.01 Cardiac fiber structuring: LV base From Torrent-Guasp, 1998 LV near the apex Silico.6.01 Rabbit Heart: Epicardial fibers – blue Subendocardial fibers - yellow From Vetter and McCulloch, UCSD Silico.6.01 Integration by Computation: The Cardiome • Transport: • UW: Flows, uptake (O2, fats) • Cardiac Mechanics: • Auckland Univ: P.Hunter • UCSD: McCulloch • Maastricht: Arts, Prinzen, Reneman • JHU: W.Hunter • Action Potentials: • Oxford U: D. Noble • Johns Hopkins: Winslow • Case-Western: Rudy • Cardiac excitatory spread: • • • • CWRU: Rudy et al. Johns Hopkins: Winslow Syracuse: Jalife UCSD: McCulloch N.Smith, P. Hunter,et al. 1998 Silico.6.01 What are the mechanisms for the responses in Left Bundle Branch Block? Thallium scans: How is local flow regulated? PET Glucose Uptake: How is glycolysis regulated? MR Strain Patterns: How do structure, excitation, and contraction combine to produce these? X-ray LV hypertrophy: What regulates actin and myosin expression? Silico.6.01 Excitation-Contraction Coupling • Cooperativity • Mechanical Feedback Silico.6.01 The Motor Units Silico.6.01 Energy Use depends on shortening velocity: g +g V 0 1 ATP ATP ADP WEAK f STRONG Weak-Strong vs. Attached-Detached Mechanical Feedback Landesberg/Sideman, 1998 Silico.6.01 The Conservative Phys-chem cell (no protein synthesis or proteolyis) • Balances mass, charge, volume, energy, reducing equivalents, concentrations • Serves as a primitive for expanded models • • • • • RBC, prokaryote, eukaryote, myocyte, B-cell Serve as entry to databases Component of healthy and diseased tissues Basis for multicellular integrated systems models Understanding via metabolic control analysis of networks • Test bed for mechanistic pharmacodynamic models and selection for drug design and for genomic intervention Silico.6.01 The glycolytic conservative cell (with eternal proteins) e.g. arep.med.harvard.edu, Edwards, Palsson,Church et al. Ca2+ Substrates 3Na+ ATP Metabolites Ca2+ Ca2+ K+ Glycolysis RBC pH balance ~P balance Purine balance Osmotic balance Water balance Charge H+ neutrality Na+ Redox state calmodulin Free Energy Na+ 3Na+ ATP H+ 2 K+ Silico.6.01 The conservative cell with eternal proteins Substrates INaCa Ip(Ca) ATP Na+ Ca2+ Glycolysis, fatty acid TCA OxPhosph Endoplasmic reticulum pH ~P balance Purine balance Osmotic balance Water balance ATP Na+ Na+ Ca2+ K+ Charge H+ neutrality Redox state calmodulin Free Energy Na+ ATP H+ K+ INaK INa Silico.6.01 The sustainable metabolic muscle cell ICa,b ICa,K Substrates INaCa Ip(Ca) OxPhosph TCA ATP Ca2+ Na+ Ca2+ K+ Ca2+ T-tubule ICa subspace K + K Ca2+ + RyR calseq Ca2+ Sarcoplasmic reticulum ATP regulation pH, P & K + Charge K neutrality + calmodulin Leak Ca2+ K TRPN + Na+ Ca2+ IKs IK1 IKp calmodulin Ca2+ ATP IKr Na+ Na+ Na+ INa INa,b Ito1 ATP H+ K + INaK Silico.6.01 The cardiac muscle cell ICa,b ICa,K Substrates INaCa Ip(Ca) ATP Ca2+ T-tubule ICa subspace Na+ Ca2+ K+ Ca2+ K Glycolysis + RyR calseq K OxPhosph TCA Ca2+ + K calmodulin Ca2+ IK1 + IKp K Leak Sarcoplasmic reticulum + ATP Na+ Ca2+ Na+ Na+ Na+ INa INa,b IKs + K Ca2+ IKr Ito1 ATP (building from Luo-Rudy 1994-2001 and Winslow et al. 1999) H+ K + INaK Silico.6.01 Conclusions: • Conservative cell models provide a basis for a host of specific applications. • Their behavior is innately complex and highly dependent on the conditions. • Computability is a major issue if models are to be used are practical aids to thinking. • Even now they provide short-term prediction of the consequences of intervention. Silico.6.01 END www.physiome.org Silico.6.01