NIH funds IU collaboration to develop computational model of acetaminophen-induced liver failure

Multiscale modeling also seen as means of reducing use of animals in toxicity studies

  • Dec. 3, 2014


BLOOMINGTON and INDIANAPOLIS, Ind. -- Three Indiana University professors have received $2.1 million to develop a computational model of acetaminophen-induced liver failure -- the leading cause of liver failure in the United States -- by using advanced microscopic and computational technologies that allow scientists to see into the liver of a living animal.

James A. Glazier, director of IU’s Biocomplexity Institute and a professor of physics in IU Bloomington's College of Arts and Sciences; James Klaunig, an environmental health professor in the IU School of Public Health-Bloomington; and IU School of Medicine professor of nephrology Kenneth Dunn will work together to develop computational biology models of liver toxicity. The research is considered by the National Institutes of Health as a first step in the development of new technologies capable of predicting the toxicity of therapeutic agents and environmental toxins while simultaneously reducing the use of animals in toxicity studies.

While funding is being provided through the NIH, the research is an outgrowth of a consortium of six federal agencies called the Interagency Modeling and Analysis Group that are working together to promote scientific partnerships focused on increasing the impacts of multiscale modeling.

Multiscale modeling uses mathematics and computation to quantitatively represent and simulate a system at more than one scale while functionally linking the mathematical models across scales that range from molecular, cellular and tissue to organ, whole-body and population.

The models can be designed to integrate diverse data; create testable hypotheses leading to new investigations; identify and share gaps in knowledge; uncover biological mechanisms; or make predictions about clinical outcome or intervention effects. NIH believes the ultimate goal is being able to make realistic scientific predictions to address problems and issues in the environment and in the human body.

“Multiscale models of biological and behavioral systems can be used as important tools to address a range of biomedical, biological, behavioral, environmental and clinical problems,” Glazier said. “And they inherently provide a fundamental infrastructure for understanding and predicting biological and environmental processes, diseases, and human and organizational behavior patterns and outcomes.”

Understanding liver toxicity could be the key to also understanding the toxicity of drugs and environmental pollutants. If this computational biology modeling effort succeeds, it could pave the way for additional multiscale models being used to prevent, diagnose and treat other diseases or aberrations in normal development, and to predict treatment outcomes.

The three researchers will each lead teams -- two focusing on experimentation and one on modeling -- that together bring multidisciplinary expertise in computation biology (Glazier), advanced microscopic imaging techniques (Dunn) and extensive chemical and biological expertise in pharmacology and toxicology (Klaunig).

They said they chose to simulate the liver because it is a key organ in many toxicological, pharmacological, normal and disease processes; and use acetaminophen as the organ’s toxic challenge as it is the most widely used over-the-counter pain reliever and fever reducer in the U.S., with over 25 billion doses sold annually. Available over-the-counter in the U.S. since 1960, acetaminophen is a frequent component in many over-the-counter and prescription combinations with decongestants, antihistamines, sleeping aids and other analgesics such as oxycodone, hydrocodone, dilaudid and codeine.

The research, including computer simulations calibrated using microscopic imaging in the liver of a living mouse, will be conducted at IU laboratories in both Bloomington and Indianapolis. Federal agencies in addition to NIH that are participating in the Interagency Modeling and Analysis Group funding the work include the National Science Foundation, the Food and Drug Administration, the National Aeronautical and Space Administration, the Department of Defense and the Department of Energy.

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A multiphoton microscopy image of liver cells in a healthy rat. Red identifies sinusoids, blue denotes cell nuclei, dim green are hepatocytes and bring green are bile canaliculi.

A multiphoton microscopy image of liver cells in a healthy rat. Red identifies sinusoids, blue denotes cell nuclei, dim green are hepatocytes and bring green are bile canaliculi. | Photo by Kenneth Dunn, IU School of Medicine

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Stephen Chaplin