Research Seeks to Discover Fundamental Truths about a Leading Contributor to Disease and Death

Research Seeks to Discover Fundamental Truths about a Leading Contributor to Disease and Death

When you cut your skin, your body’s ability to produce protein fibers like collagen to close the wound can save your life. But when scarring occurs in a vital organ—either in response to an injury or through a flaw in the healing process—it can lead to disease and death.

Excess scarring, or fibrosis, is implicated in dozens of conditions. Cirrhosis of the liver, pulmonary fibrosis and muscular dystrophy are among the many fatal diseases in which fibrosis plays a major role. Fibrosis was recently estimated to be involved in or responsible for as many as 40 percent of all deaths worldwide.

When Professor Thomas Barker, an expert in pulmonary fibrosis, joined the University of Virginia Department of Biomedical Engineering this fall, his brief was not only to expand his campaign to find more effective treatments for the disease, but also to mobilize the considerable fibrosis expertise in the department and the UVA School of Medicine.

“Because of the variety of fibrosis research underway here, we have an opportunity to discover fundamental rules of fibrosis that transcend tissue types,” Barker said. “This could lead to new therapies that can be applied to multiple fibrotic disorders.”

Imperfect Healing

Under normal conditions, collagen and similar proteins are secreted by cells to produce scaffolding called the extracellular matrix (ECM), which not only provides structural support to surrounding cells, but also segregates different kinds of tissue from one another. Barker notes that a cancer cell’s ability to destroy the ECM is one of the conditions that allows it to spread to new organs.

The ECM can also determine a cell’s biochemical responses to its environment. Physical changes in a cell’s environment, for example, can cause it to produce enzymes that release growth factors stored in ECM, which in turn can stimulate the cell to produce additional ECM.

Different tissue types have evolved with unique ratios of cells to ECM, ideal mixtures of stiff ECM proteins like collagen and flexible proteins like elastin, and characteristic ECM designs. During wound repair, however, cells secrete and assemble ECM with less than optimal composition and design, changing its properties. The scar that develops in the heart after an attack has none of the flexibility of muscle tissue. This stiff region of a chamber’s wall distorts the way the heart pumps and can ultimately lead to heart failure.

In other cases, ECM production is not stimulated by a wound, but by a change in a cell’s ability to properly sense its environment, causing it to go into what Barker calls “permanent repair mode.” Barker uses a number of methods to tease out the causes of this disregulation, to interrupt the feedback loops that cause excessive ECM deposition and to modify the scar tissue it produces so it has less effect on tissue function.

In recognition of the quality of this research, the American Society for Matrix Biology presented Barker with its 2016 Renato Iozzo Award, its premier mid-career award. He previously won the society’s Junior Investigator Award in 2012.

Asserting UVA Leadership in Fibrosis Research

Barker’s first year at UVA promises to be busy. He arrived at UVA from Georgia Institute of Technology with a $3.5 million National Institutes of Health (NIH) Director’s Transformative Research Award to rewire the genetic processes that cause pulmonary fibrosis. In the presence of stiff scar tissue, cells tend to generate more scar. Barker is exploring methods to hijack this response, inducing cells to produce enzymes that would cut collagen fibers and reduce the cross-linking that gives scars their stiffness.

A more recent grant from the NIH illustrates the breadth of Barker’s expertise. Uncontrolled bleeding is the major cause of death from traumatic injury, and bleeding following invasive surgeries such as cardiopulmonary bypass dramatically increases the risk of damage and death. His goal is to develop synthetic platelet analogs to selectively enhance clot formation and clot stabilization.

During the spring, Barker will launch a Grounds-wide fibrosis initiative to bring together faculty members who are working on fibrosis to share ideas. “We hope the cross-fertilization of ideas will lead to new proposals and a wider recognition for UVA in the field,” he said.