Thursday March 21, 2013, 11:00am - noon EST

Towards predictive quantitative modeling of tissue organization and tumor growth on histological scales by imaging, image analysis and modeling

Dirk Drasdo, Stefan Hoehme, Jan G. Hengstler, Rolf Gebhardt, Ursula Klingmueller, Jens Timmer

A major challenge is to understand how cells and molecules act coordinately together to form complex functional tissue architectures and which processes are perturbed in aberrant states. While in-vitro systems, frequently considered as model systems may help in identifying candidate mechanisms that may act in-vivo, the increased complexity of the in-vivo system of interest – usually a patient – ultultimately require in-vivo validation. We propose a mathematical modeling - guided experimental strategy to optimize and economize the choice of experiments that address tissue organization and growth processes. Our procedure is based on a recently established process chain composed of confocal laser scans, image processing and three-dimensional tissue reconstruction, as well as on quantitative mathematical modeling resolving tissue architecture (Hoehme et. al., PNAS, 107:10371-10376, 2010). We demonstrate how by iterative application of this procedure a final mathematical model could be constructed that unambiguously predicted a previously unrecognized order mechanism in liver regeneration. The model prediction has subsequently been experimentally validated. The model has been further used to calculate the spatial temporal pattern of ammonia detoxification during the regeneration process. We then use this model to simulate early genesis of primary tumors in liver in small animals. The simulations show that hepatocytes lacking cell cycle entrance control form an – experimenntally observed - tumor phenotype that reflects the order mechanism. If the order mechanism is compromised, another tumor phenotype forms which is very robust against changes of other parameters such as cell-cell adhesion, micro-motility etc.. The signature of the order mechanism gets lost once the tumor size overcomes the size of a single liver lobule. A fundamental problem is in how far findings in an animal model can be transferred to human as validation experiments in human are particularly difficult to perform. We finally illustrate that our mathematical model, firstly calibrated with static and dynamic mouse data, and in a second step re-calibrated with only static pig data, provides a valid prediction for liver regeneration after partial hepatectomy in pig. This may serve as a first proof-of-concept step to use models of tissue organization to extrapolate from an animal model to patients.

Wednesday, November 14, 2012 at 12:30pm ET

Modeling cardiac function and dysfunction

Natalia Trayanova, PhD, Johns Hopkins University

Simulating cardiac electrophysiological function is one of the most striking examples of a successful integrative multi-scale modeling approach applied to a living system directly relevant to human disease. This presentation showcases specific examples of the state-of-the-art in cardiac integrative modeling, including 1) improving ventricular ablation procedure by using MRI reconstructed heart geometry and structure to investigate the reentrant circuits formed in the presence of an infarct scar; 2) developing a new out-of-the box high-frequency defibrillation methodology; 3) understanding the contributions of non-myocytes to cardiac function and dysfunction, and others.

Archived Recording: https://webmeeting.nih.gov/p75536528/

Monday, September 17, 2012 at 1pm ET

Multi-Scale Modeling of Sickle Cell Anemia

George Karniadakis, PhD, Brown University

Presentation Slides

Sickle cells exhibit abnormal morphology and membrane mechanics in the deoxygenated state due to the polymerization of the interior sickle hemoglobin (HbS). We study the dynamics of self-assembly behavior of HbS in solution and corresponding induced cell morphologies by dissipative particle dynamics approach. A coarse-grained HbS model, which contains hydrophilic and hydrophobic particles, is constructed to match the structural properties and physical description (including crowding effects) of HbS. The hydrophobic interactions are shown to be necessary with chirality being the main driver for the formation of HbS fibers. In the absence of chain chirality, only the self-assembled small aggregates are observed whereas self-assembled elongated step-like bundle microstructures appear when we consider the chain chirality. Several typical cell morphologies (sickle, granular, elongated shapes), induced by the growth of HbS fibers, are revealed and their deviations from the biconcave shape are quantified by the asphericity and elliptical shape factors.We then use these sickle cells to study the rheological properties of sickle blood and the adhesive dynamics between red blood cells, white cells, and the arterial wall in small arterioles.

Archived Recording: https://webmeeting.nih.gov/p78189808/

Friday June 8, 2012 at 1:00pm ET

Specification, Construction, and Exact Reduction of State Transition System Models of Biochemical Processes

Scott M. Bugenhagen and Daniel A. Beard, PhD

In this presentation, we introduce methods for the high-level specification of a system using hypergraphs, for the automated generation of a state-level model from a high-level model, and for the exact reduction of a state-level model using information (viz. symmetries and invariant manifolds) from the high-level model. We then give a tutorial demonstration of the practical application of the methods to the modeling of biochemical reaction systems using several examples constructed using Vernan, a MATLAB tool implementing the methods.

Archived Recording: https://webmeeting.nih.gov/p65832122/

Friday October 28, 2011 1-2pm ET

Kasia A. Rejniak, PhD, H. Lee Moffitt Cancer Center & Research Institute

Title: Computational Bridging of Epithelial Morphogenesis and Tumor Mutations

A major challenge in biology is the mapping of genotypic changes to phenotypic outcomes. I will present how a computational model of epithelial morphogenesis (IBCell) can address this problem by linking molecular alterations to epithelial morphology through cellular core traits. In particular, I will show an example in which IBCell interrogated with 3-dimensional experimental acinar morphologies of breast epithelial cells expressing a mutant HER2 receptor leads to identification of previously unknown core trait alterations, i.e., loss of negative feedback from autocrine secreted ECM. I will also briefly show other applications of the IBCell model.

Lance L. Munn, PhD, Massachusetts General Hospital & Harvard Medical School

Title: Imaging vascular dynamics

Although therapies targeting the vasculature have had growing popularity in the past decade, we still know surprisinlgy little about how vasculature is formed or remodeled in plastic tissues such as wound beds or tumors. Intravital microscopy in transparent windows has the potential to reveal how cells organize and cooperate to accomplish critical processes such as morphogenesis and anastomosis. Facilitated by the recent availability of in vivo reporters and time-lapse imaging which allow tracking of specific cell populations, intravital microscopy is a powerful tool for determining cellular mechanisms of vascularization and tumor growth.

Tuesday May 31, 2011 11am-12pm ET: The Cardiovascular System and Disease

Nic Smith, Kings College London. Translating multi-scale modelling to the Heart of the clinic: developing personalised cardiac models

Michael King, Cornell University. Multiscale model of platelet adhesion and thrombus formation: validation with the humanized mouse