ROCHESTER, Minn. — In cell and mouse models, Mayo Clinic researchers and collaborators have identified a way to slow and reverse the process of uncontrolled internal scarring, called fibrosis.

This disease process has few effective therapies, no cure and can be fatal when it occurs in organs such as the liver (cirrhosis) or lungs (pulmonary fibrosis). The findings appear Wednesday, Oct. 30, in Science Translational Medicine.

a medical illustration of fibrolasts (blue) release collagen (white) to repair tissue damage from fibrosis.
Fibroblasts (blue) release collagen (white) to repair tissue damage. In the disease process of fibrosis, fibroblasts release collagen in amounts that interfere with a tissue’s function.

In the past, researchers identified two proteins that regulate gene action and provide “instructions” for fibrosis, called yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). However, YAP and TAZ are involved in too many other beneficial actions and can’t be universally blocked. So the scientists, led by Daniel Tschumperlin, Ph.D., a Mayo Clinic researcher, focused on cells that form the scar tissue, called fibroblasts. After an injury, these cells migrate to the damaged area and produce collagen to re-form the scaffolding around cells and repair tissue. In fibrosis, fibroblasts release collagen in amounts that interfere with an organ’s function.

“We
started this work almost five years ago with seed funding from Mayo’s Center
for Biomedical Discovery
because fibrosis is an important and poorly
understood disease process,” explains Dr. Tschumperlin. “We had
identified the transcriptional regulatory proteins YAP and TAZ as important to
the progression of fibrosis, but there were no viable approaches to target this
pathway for therapy.”

The
publication reports on a new target: a dopamine receptor. The authors found
that the receptor is unique to lung and liver fibroblasts. Stimulating it
blocks YAP and TAZ, reducing and reversing the growth and scar-forming
abilities of fibroblasts. Stimulating the dopamine receptor in fibroblasts
appeared to switch them from a matrix-depositing state that supports fibrosis
to a matrix-degrading state that supports resolution or reversal of fibrosis.
In lung and liver fibrosis models, the approach reversed the fibrotic process
in these organs.

“Dopamine
is mostly studied in disorders of the central nervous system, and we were
surprised to find dopamine receptors expressed in fibroblasts,” says Dr.
Tschumperlin. “We also found that the lung may be able to produce dopamine
locally, and this function appears to be compromised in individuals with
pulmonary fibrosis. Thus, the pathway we are targeting might be part of a
normal response that would limit fibrosis, but is somehow missing in patients.”

This
result, the researchers say, opens up a new treatment concept for fibrotic
disease conditions. They hope to build on the decades of work that already has gone
into developing dopamine receptor-targeting drugs in the brain to develop new
dopamine-related therapies for fibrosis. “In addition to following up on regulation
of dopamine signaling in the lung, we are actively developing novel molecules
to target the dopamine receptor, as we think there is substantial promise in
trying to translate this approach to human diseases,” says Dr.
Tschumperlin.

Other
authors of the paper include collaborators from the University of Pittsburgh,
Massachusetts General Hospital/Harvard Medical School, and Boston University
School of Medicine. In addition to Dr. Tschumperlin, other Mayo authors are Andrew
Haak, Ph.D.; Enis Kostallari, Ph.D.; Delphine Sicard, Ph.D.; Giovanni Ligresti,
Ph.D.; Kyoung Choi, Ph.D.; Nunzia Caporarello, Ph.D.; Dakota Jones, a student
in Mayo Clinic Graduate School of Biomedical Sciences; Qi Tan, Ph.D.; Jeffrey
Meridew; Ana Diaz Espinosa; Aja Aravamudhan, Ph.D.; Jessica Maiers, Ph.D.; Rodney
Britt Jr., Ph.D.; Anja Roden, M.D.; Christina
Pabelick, M.D.
;
Y.S. Prakash,
M.D., Ph.D.
;
and Vijay Shah, M.D.

Funding
for this work was provided by federal and nongovernmental sources, as listed in
the publication, and support was provided by Mayo Clinic’s
Center for Clinical and Translational Science
.

The
first author, Dr. Haak, and Dr. Tschumperlin disclose that they are
co-inventors of a patent application based on some of the findings in the
publication.

###

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