Case Western Reserve University has established a new Center for Modeling Integrated Metabolic Systems (MIMS), funded with a five-year, $11.9 million grant from the National Institute of General Medical Science, an arm of the National Institutes of Health.

The MIMS center is one of two new enterprises recently established by the NIH to encourage computational approaches to deepen the nationwide scientific understanding of complex biological processes.

MIMS center researchers use mathematical modeling and computer simulation to analyze changes in cellular metabolism of the heart, skeletal muscle, brain and liver as well as their integrated effects in the human body. The metabolic changes of interest are associated with exercise, diet and disease.

Collaborations in the MIMS center involve six faculty from CWRU and two from Cleveland State University (CSU) with complementary expertise in computer modeling and biological experimentation.

"Center experts use computers to solve thousands of mathematical equations, simulate complex biological functions, interpret experimental data and make quantitative predictions for understanding abnormal function," said Professor Gerald M. Saidel of the Department of Biomedical Engineering, who is also Director of the MIMS Center.

"The MIMS center's multidisciplinary team will contribute to the development of quantitative tools to analyze complex biological mechanisms at the root of many serious health problems," Saidel said. These tools include advanced numerical methods for faster computer simulation being developed by CWRU Professor of Mathematics Daniela Calvetti.

In addition to cutting-edge research, the MIMS center will offer an annual symposium or workshop on modeling integrated metabolic systems that will be open to researchers from around the globe. It also will provide educational and work opportunities for CWRU undergraduates, graduate students and post-doctoral research associates.

"The center will help develop a new generation of researchers who will be able to deal with complex biomedical systems by applying sophisticated modeling for the analysis of experimental data," Saidel said. "These young investigators will learn to test hypotheses quantitatively by performing optimally designed experiments and using computational models for integration, interpretation and prediction."

MIMS center researchers point out that computer modeling is becoming more common in analyzing complex biomedical problems because of the availability of high-performance, low-cost computers with large storage capacity. "The center's system modeling and integration ability will help scientists understand the interaction of the metabolic pathways in organs and tissues as well as their integrated responses in the context of the whole body," said Associate Director of the MIMS Center Marco E. Cabrera. Cabrera also is an assistant professor of pediatrics, biomedical engineering, and physiology and biophysics at CWRU and a scientist at the Research Institute of the University Hospitals of Cleveland (UHC).

MIMS research Leaders and New Directions

Professor Gerald Saidel will take a leadership role in model development and data analysis for all research projects as well as collaborate in the Center's two core areas: systems modeling integration and computational methods of large-scale systems. In addition, he also will direct education, research and training at the MIMS Center. Saidel has a broad background in computer modeling and experience essential for analyzing complex metabolic systems.

The research of Professor Marco Cabrera focuses on elucidating mechanisms for regulating muscle metabolism during exercise to improve daily functioning of pediatric patients with chronic cardiovascular or pulmonary disorders. "Non-invasive experiments that patients can perform without difficulty are analyzed using computational models of muscle metabolism," said Cabrera. "This approach is practical and provides insights into the mechanisms of cellular metabolic regulation."

Cabrera will be responsible for both the experimental and modeling aspects of skeletal muscle metabolism. He also will direct the Center's main core in systems and modeling integration.

Professor Henri Brunengraber, chair of the Department of Nutrition at the CWRU School of Medicine, leads the experimental studies of liver metabolism emphasizing the regulation of fat synthesis. According to Brunengraber, liver cells (hepatocytes) are arranged in cylinders through which blood passes. Consequently, exchanges between hepatocytes and blood alter the chemical composition of blood and hepatocytes.

"We will use mathematical models to account for these processes which will help in our understanding liver diseases," Brunengraber said.

Brunengraber is collaborating with Joanne M. Belovich, Associate Professor of Chemical Engineering at CSU and an expert in modeling of cellular metabolism, who will lead the computer modeling effort in liver metabolism.

Joseph C. LaManna, Professor of Neurology , chair of the Department of Anatomy, CWRU School of Medicine, and Scientist at the Research Institute of the University Hospitals of Cleveland, conducts experimental studies on metabolic brain function. He examines energy demand, energy metabolism and blood flow in the brain to evaluate the brain's response to pathological insults such as stroke, hypoxia and seizures.

"Because the regulation of brain metabolism and blood flow involves complex control systems with many interacting variables at the cellular and organ level, a computational model of the brain is essential," Professor LaManna said. "Our computational model will quantify fundamental mechanisms that are important in designing therapeutic strategies to reverse neurological dysfunctions associated with stroke and epileptic seizures."

Lamanna is collaborating with Jorge E. Gatica, Associate Professor of Chemical Engineering at CSU, who is an expert in chemical reaction systems and is primarily responsible for computer modeling and simulation of brain metabolism.

William C. Stanley, Associate Professor of Physiology and Biophysics, CWRU School of Medicine, guides the MIMS Center's experimental studies in metabolism of the heart. Professor Stanley's research is aimed at understanding factors regulating myocardial metabolism during the transition from normal resting conditions to exercise stress especially without adequate blood flow. His research assesses how the heart functions with increased work under disease conditions such as coronary artery disease.

"The MIMS Center provides resources to develop more realistic computational models of cardiac function and metabolism for quantitative analysis and design of experiments," said Stanley. This research is done in collaboration with Cabrera, who is responsible for computer modeling and simulation of cardiac metabolism.