Epithelial progenitors and the stromal niche as therapeutic targets in lung disease

Chronic lung disease is an enormous societal and medical problem in California and the nation as a whole, representing the third most likely cause of death with treatment costs of $389.2 billion in 2011 and expected to reach $832.9 billion in 2021 according to the Milken Institute. Chronic lung diseases cover a spectrum of disorders that include pulmonary fibrosis, a disease that makes it difficult to breathe due to the accumulation of scar tissue in the lung, and chronic obstructive pulmonary disease (COPD), a disease that makes breathing difficult due to loss of critical structures that allow oxygen to enter the blood. According to Breathe California, COPD is the 4th leading cause of death in the United States and 1.6 million Californians are diagnosed with COPD. Treatment options vary by disease but are particularly ineffective for patients with COPD and fibrotic lung diseases. One fibrotic lung disease termed idiopathic pulmonary fibrosis (IPF) can only be treated by lung transplantation and this option is limited to those who meet specific age and health criteria. Without transplantation the majority of IPF patients die within three years of initial diagnosis. Our research program has relocated from Duke University Medical Center to Cedars-Sinai Medical Center with the goal of translating a basic understanding of disease mechanisms to improved patient care. We have developed new tools to understand cell types and regulatory mechanisms that participate in lung repair and disease in mouse models. These new mouse models allow us to investigate ways that lung cells interact to repair damage in an intact animal model, and have allowed us to develop new ways of reconstructing regulatory cell interactions in a culture environment. Parallel culture models for analysis of human lung cell types have allowed us to investigate the critical roles for cell-cell interactions in the regulation of epithelial repair and aberrant tissue remodeling. Our long-term goal is to determine how lung disease is caused and use this information to develop new therapies that will prevent either initiation or progression of lung disease.

Reporting Period:

Year 2

Reporting Period:

Year 3

Our research program seeks to identify reparative cells of the lung that contribute to normal maintenance and repaired after injury, determine how they are regulated at the molecular level, and to determine how and why these cells are disregulated in lungs of patients with chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Our long-term goal is to determine how lung disease is caused and use this information to develop new therapies that will prevent either initiation or progression of lung disease. We have made progress in studies using mouse models to investigate lung repair mechanisms and also with human samples to understand how lung tissue stem cells change in patients with lung disease. In animal studies we have defined cells that migrate within the lung to repair damage caused by severe H1N1 influenza virus infection. Over our last funding period we discovered that the immune response to viral infection plays an important role in changing epithelial cells to enhance repair of damage. This novel data could provide new ways of activating lung tissue repair mechanisms to promote lung regeneration. Our work with patient samples has allowed us to identify molecular signatures of normal lung cell types that line airspaces of the lung and molecular changes to these cells seen in IPF. We have developed mouse models to further explore disease mechanisms and are using these models to define potential therapeutic targets that may alter disease outcome. We have made significant progress in the development “lung in a dish” models for human cells and have established methods for the generation of lung cell types from patient-specific pluripotent cells (a type of stem cell that has the potential to generate all cells of the body). Continuation of this work will provide new model systems and a more comprehensive understanding of molecular changes to lung cells that accompany disease. This information will allow us to define new targets for drug development and opportunities to help patients with intractable lung diseases.

Reporting Period:

Year 6

Grant Application Details

Application Title:

Epithelial progenitors and the stromal niche as therapeutic targets in lung disease

Public Abstract:

Chronic lung disease is an enormous societal and medical problem in California and the nation as a whole, representing the third most likely cause of death. Treatment costs were $389.2 billion in 2011 and are expected to reach $832.9 billion in 2021 according to the Milken Institute. Chronic lung diseases cover a spectrum of disorders that include pulmonary fibrosis, a disease that makes it difficult to breathe due to the accumulation of scar tissue in the lung, and chronic obstructive pulmonary disease (COPD), a disease that makes breathing difficult due to loss of critical structures that allow oxygen to enter the blood. According to Breathe California, COPD is the 4th leading cause of death in the United States and 1.6 million Californians are diagnosed with COPD. Treatment options vary by disease but are particularly ineffective for patients with COPD and fibrotic lung diseases. One fibrotic lung disease termed idiopathic pulmonary fibrosis (IPF) can only be treated by lung transplantation and this option is limited to those who meet specific age and health criteria. Without transplantation the majority of IPF patients die within three years of initial diagnosis.

Our research team being recruited to California is led by an international expert in lung stem cell biology and includes a leading physician in pulmonary fibrosis research and clinical management. Goals of research outlined in this proposal are to understand how lungs are damaged by diseases and to develop new treatment options to help prevent, arrest, or repair damage leading to
improved patient health. Specifically, we will show how cells that line airspaces of the lung generate new cells that function to protect the lung from injury and facilitate gas exchange during breathing. Through this work it will be possible to determine how lung disease is caused and this will lead to new therapies that will prevent either initiation or progression of lung disease.

Statement of Benefit to California:

Lung disease has an enormous societal impact. For the period from 1990-2008 chronic lower respiratory diseases were the third most likely cause of death in the US, accounting for approximately 6% of deaths and an annual rate of approximately 0.1% of the total population (NHLBI report, 2010). Lung diseases can be caused by either genetic and/or environmental factors, and are compounded by age-related declines in lung function. Poor air quality in and around major California cities are well documented and have been conservatively estimated to account for 10,000 hospital visits per year (RAND Corporation report, 2010). Ozone and particulate airborne pollutants are a significant concern due to chronic effects on lung tissue remodeling in otherwise healthy individuals. They also trigger exacerbations in patients with existing lung disease leading to more serious illness and death. Interventions can include imposing strict air quality standards and improving therapies for patients either with or who are at risk of developing lung disease. Pulmonary fibrosis in particular represents a major unmet medical need in California and lung transplant is the only effective therapy at present. Accordingly, defining mechanisms of lung fibrosis and developing cures for otherwise intractable lung diseases has the potential to significantly benefit the population of California. This CIRM Research Leadership Award application will develop a transformative program aimed at applying new discoveries in basic mechanisms of lung disease towards development of new interventions to help patients. This will be accomplished by integrating the applicant’s expertise in lung stem cell biology and regenerative medicine with basic and translational research strengths at the destination institution. Previous work has shown that signaling interactions between epithelial progenitor cells and their associated stromal microenvironment are critical for normal development and tissue homeostasis in adulthood. These interactions are dysregulated in many lung diseases including fibrotic lung diseases, chronic obstructive pulmonary disease and asthma. This proposal will focus on fibrotic lung diseases in particular due to the poor prognosis that results from lack of effective therapies. Through identifying mediators that regulate epithelial progenitor-stromal interactions in the normal adult lung, and how changes in their activity contribute to disease, we will gain new insights into disease mechanisms and therapies. We expect that discoveries will be broadly applicable to many lung diseases and will significantly impact Californians through novel drug discoveries that improve the health and quality of life of patients with early onset or established lung disease.

Publications

Sci Rep (2016): Distal airway epithelial progenitor cells are radiosensitive to High-LET radiation. (PubMed: 27659946)
Radiat Res (2015): Low- and high-LET radiation drives clonal expansion of lung progenitor cells in vivo. (PubMed: 25564721)
Cell Stem Cell (2015): A new notch for lung stem cells. (PubMed: 25658364)
Cell Rep (2016): p53 Regulates Progenitor Cell Quiescence and Differentiation in the Airway. (PubMed: 27880895)
Stem Cell Reports (2016): Rare SOX2+ Airway Progenitor Cells Generate KRT5+ Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection. (PubMed: 27773701)
Development (2017): Sin3a regulates epithelial progenitor cell fate during lung development. (PubMed: 28619823)
JCI Insight (2016): Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. (PubMed: 27942595)