Consortium for Fibrosis Research and Translation
Transformational Research Funding
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 failure.
The Opportunity
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.
Existing Strengths
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.
Vascular 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
Pre-Clinical 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.
ibrosis 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 molecular levels.
Computational Biology Unit will support the syncing of whole transcriptome data from fibrotic human tissues with detailed patient phenotypic data.
Clinical Discovery 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
Specific Aims
Establish new internal collaborations that lead to enhanced extra mural funding.
Establish unique industry partnerships and philanthropic opportunities.
Establish a training environment that enhances institutional strengths in education.
Nominate a novel anti-fibrotic therapy for Phase IIa testing in humans.
Leadership
Director Tim McKinsey, PhD
Co-Director Mary Weiser-Evans, PhD