Fibrosis is a common feature of many chronic diseases
where repetitive injury or discrete pathological stressors stimulate an
increase in extracellular matrix deposition. While fibrosis has a well-accepted
role in the development of numerous diseases, there are only two FDA-approved
anti-fibrotic therapies and the efficacy of these treatments is limited, with
no impact on quality of life, symptoms or mortality. It is estimated that 45
percent of deaths in the developed world are due to fibrosis-induced organ
The Consortium for Fibrosis Research and Translation (CFReT)
is the first of its kind in the United States, integrating within a single
institution experts in the molecular mechanisms and treatment of fibrotic
diseases across organ systems. Investigators will focus on fibrotic heart,
kidney, lung and liver diseases, as well as the vascular fibrosis underlying
failure in these organs.
The University Colorado Denver (UCD) possesses unique
strengths in many areas relevant to fibrosis, but the institution has yet to organize
efforts focused on this important field.
Anschutz Medical Campus investigators have a long and
productive history of basic, translational and clinical research programs
focused on cardiac fibrosis and
associated heart failure. Lab work here centers on the
roles of epigenetic mechanisms and upstream signaling events in the control of
cardiac fibroblast activation. Bridging basic science with human clinical
studies, another existing laboratory investigates the molecular mechanisms
involved in the genesis and progression of pathologic cardiac hypertrophy,
contractile dysfunction, and fibrosis, which are hallmarks of chronic heart
failure. To complement their studies, this group has assembled the world’s
largest and best-characterized bank of fibrotic, explanted human heart tissue,
and normal control hearts. Finally, clinical studies in another laboratory
focus on reverse remodeling of the left ventricle (LV) in heart failure
patients implanted with LV assist devices (LVADs).
Additional research on campus is devoted to defining the mechanisms
regulating obesity- and diabetes-induced fibrosis in the kidney, liver,
aorta, and heart. Current interests include the regulation of renal and
intestinal phosphate transport in CKD, and the role of nuclear hormone and
G-protein coupled receptors in the regulation of vascular fibrosis. The long-standing PKD Center continues to
conduct clinical trials focusing on fibrosis in chronic kidney disease
and autosomal dominant polycystic kidney disease. A pre-clinical and translational
program in polycystic kidney disease has been established.
Other research focuses on the mechanisms of lung injury and repair.
Cell culture systems and pre-clinical models of acute lung injury and pulmonary
fibrosis are used to determine the mechanisms and signaling pathways involved
in dysfunctional repair of alveolar epithelial cells, which leads to fibrotic
lung disease. Murine models of lung
disease are used in additional labs to understand the immune mechanisms that
promote or protect against inflammation-mediated lung fibrosis. While in other labs, in vitro and
murine models are used to define the roles of innate and adaptive immune cells
in the promotion or resolution of liver inflammation and fibrosis.
fibrosis is central to the pathogenesis of heart, kidney, lung and liver
failure. Pre-clinical models of vascular fibroproliferative disorders are already
used on campus to identify molecular mechanisms repressing pathological
vascular remodeling and fibrosis. A major focus is on the role of resident
vascular stem cells in the maintenance of vessel homeostasis versus disease
progression. Scientists on campus have a long and successful history of
combining cell culture, preclinical mouse models, and translational human
studies to define the roles of inflammation and oxidative stress on age-associated vascular fibrosis.
Areas of Discovery
Discovery Group. The Pre-Clinical Discovery Group consists of a team of
basic and physician-scientists with common interests in elucidating the
molecular underpinnings of fibrotic diseases. This group focuses on four organ
systems: heart, kidney, lung and liver, as well as the underlying vascular
fibrosis that contributes to failure of each of these systems. A unique strength
of this group is the ability to blend molecular, biochemical and biomechanical
studies of fibrosis with state-of-the-art cell-based and in vivo models
of organ fibrosis.
Innovation Group. The Fibrosis Innovation Group is modeled after highly
successful innovation units within biotechnology companies and non-profit
research institutes. This group integrates, streamlines, and enriches existing
capabilities at the Anschutz Medical Campus, with a focus on fibrosis research.
Among the units in this group:
- Cell-Based Disease Modeling Unit focuses on creating
assays that mimic fibrosis in distinct organs, such as 3D culture of organoids,
which facilitates efforts of our scientists to uncover novel mechanisms and
therapeutic approaches for fibrotic diseases.
- In Vivo Disease Modeling Unit will assist
with validation and execution of all models of organ fibrosis in rodents. All
the necessary models are already in place within the labs of consortium faculty
members. The role of this unit is to assist with assessment of efficacy of novel
agents in these models.
- Fibrosis Quantification Unit will create a
series of standardized assays for quantifying fibrosis at the tissue and
- Computational Biology Unit will support the
syncing of whole transcriptome data from fibrotic human tissues with detailed
patient phenotypic data.
Group. The Clinical Discovery Group provides insight on unmet medical needs
related to fibrosis, poorly characterized elements of the pathogenesis of
fibrotic diseases, potential common mechanisms of fibrosis between different
organ systems, clinical trial development, and possible therapeutic approaches.
Furthermore, the Clinical Discovery Group is instrumental in biobanking human material,
characterizing human fibrotic tissue and fibrogenic cells, and correlating the
molecular data obtained with these samples to hard clinical endpoints. Finally,
members of the Clinical Discovery Group play a central role in designing and
executing Phase IIa Proof-of-Concept (POC) clinical trials to assess novel
therapeutic strategies in humans with fibrotic diseases
- Establish new internal collaborations that lead
to enhanced extra mural funding.
- Establish unique industry partnerships and
- Establish a training environment that enhances
institutional strengths in education.
- Nominate a novel anti-fibrotic therapy for Phase
IIa testing in humans.
Director Tim McKinsey, PhD
Co-Director Mary Weiser-Evans, PhD