Dr. Srba Mijailovich

Dr. Mijailovich received his PhD in mechanical engineering from the Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, in 1991. He is a Research Professor for computational mechanobiology at the Department of Biology at IIT. His research interests are in developing quantitative approaches to study biological systems at multiple levels of organization (i.e. multiscale modeling). In particular, he is leading the development of a theoretical framework that will advance our understanding of how cellular and subcellular phenomena integrate to dynamic behavior of physiological systems, based on the kinetics of underlying molecular processes. These theoretical advances are the foundation for the development of computational platforms to study the interplay between mechanical forces, cell biology, and integrated organ physiology.

1970 - 1975

University of Belgrade

Bachelor of Science

1979 - 1981

University of Belgrade

Master of Science

Thin Filament Regulation by Calcium

The contractility of striated muscle is regulated by calcium dependent azimuthal movements of tropomyosin-troponin complexes over the surface of the actin filament. Calcium regulation of muscle contraction is essential for modulating impaired muscle function in most of neuromuscular diseases. We have developed the most comprehensive models of calcium regulation that allow translation of data from the experiments in solution to contractility of muscle fibers and whole muscles.

Multiscale Models of Skeletal and Cardiac Muscle

We were inspired by new discoveries and initiated development of multiscale models by revising the basic models of muscle contraction by, for example including myofilament extensibility, and developing the models of organs using newly developed multiscale approaches. These new approaches include crossbidge kinetics, thin filament regulation and mesoscale orientation muscle fibers from diffusion spectrum magnetic resonance imaging. The software developed in the lab provides opportunities for applications in surgical planning and personalized evaluation of patient’s loss of performance in disease or with age.

1986 - 1991

Massachusetts Institute of Technology

Doctor of Philosophy

Multiscale Modeling

The principal goal of the computational mechanobiology lab is to develop a tool for the quantitative analysis of structure-function relationship in muscle over multiple length scales. Inferring disease pathophysiology from molecular dysfunction we have developed the computational platform MUSICO (Muscle Simulation Code), to enable translating structural or functional abnormalities at the nano-scale into abnormalities at the scale of the organ and organ systems.

RESEARCH INTERESTS

EDUCATION

Smooth Muscle Contraction and Regulation

The flow patterns in tubular organs are modulated by the mechanical forces acting on airway or vessel walls and causing change in their size. In order to predict realistic behavior of tubular organs under dynamic loading conditions and in the presence of active muscle force we have developed a molecular model of smooth muscle (SM) contraction including the SM regulation by calcium. As an application of this computational model we have developed a computational model of airway narrowing.  These models could lead to future development of virtual lungs or other virtual tubular organs containing smooth muscle.

General multiscale model of muscle contraction includes two inter-connected models :

  • MUSICO Platform bridging the scales from inter-atomic (~ A) to whole cell (~100-500 mm)

  • MUSICO Multiscle FEA and DSI bridging the meso-scales from molecular interactions (~ nm) to tissue (~ mm) or organ scale (tens of cm)

X-ray Diffraction in Living Cells

Small-angle X-ray diffraction is the only technique that can provide molecular level structural information from muscle tissue under hydrated, physiological conditions at the physiologically relevant millisecond time scale. The availability of spectacular quality diffraction data currently provides only limited amount of extracted information due to lack of suitable analysis and modeling tools. Newly developed tools using data from MUSICO simulations provide a novel way of extracting new information from monitoring interactions at molecular scale and muscle contractile response at macroscopic scale. For example, this approach provided, for the first time, measurement of forces acting on actin filaments in leaving cells. Continuous development of these tools is vital to allow extraction of maximum information from the X-ray data and provide the precise information about the changes in myofilament structure and function associated with myopathic diseases.

MD Simulation of Molecular Elasticity

Understanding the sub-molecular basis of crossbridge elasticity provides the foundations for the mechano-chemistry of the acto-myosin cycle, in particular, the energetics of the power stroke, the possible asymmetry of the energy landscape, and strain dependent myosin binding in the 3D sarcomere lattice. The elasticity of cross-bridge components (the myosin lever arm, the neck and the coiled coil (S2) domains) can be assessed all-atom molecular dynamics (MD) simulations. This ongoing process is updated with new atomic structures of the crossbridge components as they appear. Also, the unresolved structures, e.g. the myosin “neck' region that separates the S1 & S2 domains, can be assessed by modeling it as random chains connecting a single coil of the lever arm(s) with coiled-coil of S2 region using MD simulations. So far we have assessed the stability of the relatively simple coiled-coil by MD simulations over several ns. Overall, this approach can be used to reveal how minor differences in sequences of the S2, lever arm and neck region affect the crossbridge elasticity. Using similar MD modeling methodology, we are working on assessing the elasticity of tropomyosins and, in collaboration with Dr. Regnier’s lab, the effect of cTnI mutations on structure-function of cardiac troponin.

Computational platform MUSICO (MUscle SImulation COde) provides realistic modelling of sarcomeric system with the aim to simulate a wide variety of experimental muscle behavior. The platform...

MUSICO Consortium:

  • Michel A. Geeves - Department of Biosciences, University of Kent, Canterbury, Kent, UK

  • Michael Regnier - Department of Bioengineering, College of Engineering & UW Medicine, University of Washington The HAAM Laboratory

  • Thomas C. Irving - Department of Biology, Illinois Institute of Technology

MUSICO meso-scale models coupling FEA and DSI:

Simulating a heartbeat in whole heart is a complex, multi-scale problem. It is necessary to prescribe both, electrical and mechanical characteristics of the myocardium and It requires three principal components:

  • A multiscale model coupling molecular kinetics and its regulations with local material characters for macroscale continuous mechanics (finite element analysis).

  • Mesoscale structural organization of the heart tissue

  • Excitation- contraction coupling an essential step of electro-mechanical cardiac simulations

...

Multiple Scale Approaches for Complex Diseases

Extensive research in last a few decades provided large amount of data from animal and human studies related to many complex diseases. The data were collected at different length scales spanning genetics, protein interactions and structure, and cell, tissue and organ function. Most of the findings at any scale were directly connected to particular disease, neglecting processes at different scales that can significantly distort outcome at organ function. This partial approach led to expensive and frequently unsuccessful development of new drugs and therapies...

Neuromuscular Disease Assessment and Therapy

For monitoring health improvement or disease progression in patients with a variety of neuromuscular disorders, ranging from amyotrophic lateral sclerosis to muscular dystrophy, the development or refining muscle assessment tools is necessary. In collaboration with Dr. Rutkove, this ongoing project aims to achieve strong theory and observed data connecting muscle impedance measurements and the pathological characteristics of tissue. For example non-invasive impedance data that can be used to characterize muscle histology; impedance-based imaging systems for the real-time evaluation of muscle contractile properties; and development of effective electrical muscle stimulation technology to serve as a useful means to improving muscle condition and health. When fully developed the impedance imaging system will enable muscle health assessment during muscle contraction in real time.