University of Wisconsin
School of Medicine and Public Health

Sandbo Lab Research

Idiopathic pulmonary fibrosis (IPF) is a devastating disease that leads to progressive scarring and destruction of normal lung tissue. This progressive loss of healthy lung tissue results in shortness of breath, inability to exercise, intractable cough, and eventually death by asphyxiation within 3-5 years after the time of diagnosis. Treatments for this condition are limited and serve to slow, but not stop, the inexorable progression of the disease. The overall goal of my research is to determine how best to stop the formation of new “scar” in the lungs of patients with pulmonary fibrosis. To do so, I study activated fibroblasts (called myofibroblasts) that are the primary cells responsible for the production and formation of new scar (extracellular matrix) in the lungs of patients with IPF. I seek to determine the molecular mechanisms that mediate fibroblast activation (myofibroblast differentiation) and the formation of new extracellular matrix during pulmonary fibrosis. By elucidating these pathways, we will identify new targets for pharmacologic therapy to halt the scarring that occurs in IPF.

Our previous studies have found that in fibroblasts, profibrotic stimuli such as Transforming Growth Factor-β utilize signaling via the actin cytoskeleton, leading fibroblast activation, fibronectin and collagen deposition into the extracellular matrix, and the development of pulmonary fibrosis. We have identified two key transcription factors, Megakaryoblastic leukemia-1 (MKL1) and serum response factor (SRF), that are regulated by the actin cytoskeleton and are critical for the activation of fibroblasts in pulmonary fibrosis. We have also identified a key intracellular negative regulator of this signaling pathway, Protein Kinase A, which can be exploited to inhibit the development of pulmonary fibrosis.

Our ongoing work builds upon these past investigations. An overall theme of our current studies is determining how the previously identified intracellular signaling (via actin/MKL1/SRF) modifies cell-matrix interactions that are important for the formation of new scar. Areas of ongoing investigation include:

  1. Determining key matrix-interacting proteins that promote the formation of new extracellular matrix (scar). We have recently found that activated myofibroblasts have a heightened ability to rapidly assemble nascent fibrillar fibronectin matrix (which serves as the scaffold for new scar formation). This ability is dependent on an intact actin/MKL1/SRF signaling pathway. We now are probing the role of key MKL1/SRF regulated proteins that facilitate accelerated fibronectin matrix assembly by activated fibroblasts (myofibroblasts). Furthermore, we are probing direct disruption of myofibroblast-mediated fibronectin matrix assembly as a means of inhibiting pulmonary fibrosis in preclinical models of the disease.
  2. Determining how the precursor population for fibroblasts and myofibroblasts, lung mesenchymal cells, expands during pulmonary fibrosis, and how we may be able to attenuate this expansion by disrupting SRF in this population, thereby inhibiting pulmonary fibrosis.
  3. Characterizing the aberrant structural organization of fibrillar collagen in IPF. In collaboration with Dr. Paul Campagnola in the Department of Bioengineering, we are using second harmonic generation microscopy, which allows for label-free assessment of collagen structure. Our goal is to characterize the SHG signature of IPF lung, identify organizational features that are unique to IPF, and determine how aberrant collagen organization may correlate with disease progression in a cohort of patients with IPF. Furthermore, we are using fabricated collagen matrices which reliably recapitulate the patterns of collagen organization that are seen in IPF tissue specimens, to examine how aberrant collagen organization promotes fibroblast activation and fibrosis.