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.
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.
The candidate principal investigator (PI) is a tenured, mid-career professor and an established leader in lung science whose pioneering discoveries have laid the groundwork for the nascent field of lung stem cell/lung regeneration research. The general goal of the proposed research program is to identify determinants of lung epithelial maintenance and repair so that they might be exploited for therapeutic purposes. The PI will test the hypothesis that cellular communications between epithelial progenitors and their surroundings are essential for normal tissue homeostasis and repair, and that dysregulation of these signals leads to lung disease such as idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans syndrome (BOS). In addition, the PI plans to establish efficient methods for deriving bronchiolar and/or alveolar progenitors from human embryonic stem cells (hESC) or induced pluripotent stem cells (iPSC) for patient-specific drug screens and therapeutic applications. The applicant institution will provide support in the form of protected research time, appropriate space, access to core services, matching funds for equipment, and an expanding intellectual infrastructure in the areas of lung regenerative medicine and stem cell biology.
Research Vision and Plans
- The proposed research program addresses mechanisms of lung regeneration, which, compared to other organ systems, represents a highly understudied area of stem cell biology.
- The large amounts of data to be obtained from these studies would lead to improved understanding of the cellular and molecular mechanisms underlying lung maintenance and repair, affording a unique opportunity for therapeutic innovation.
- Chronic lung diseases represent a significant medical burden for both California and the nation as a whole. In particular, IPF and BOS are poorly understood and untreatable. New therapeutic options are sorely needed to address this critical unmet need.
- The experimental approaches draw heavily on routine laboratory techniques that, while not particularly innovative, are technically feasible and applied to new research areas.
- While the research plan is very detailed, there is little discussion of how outcomes would be analyzed, or how pitfalls would be addressed. Similarly, there were few details provided as to how data from the different aims would be integrated.
- Some reviewers questioned the extent to which the data from murine studies would prove relevant to the human condition and advised the applicant to explore additional, more creative options for testing human cells in the context of a living organism.
PI Accomplishments and Potential
- Reviewers considered the PI to be perhaps the top lung stem cell researcher in the world today, having pioneered a number of key discoveries in the pulmonary field. His/her achievements have been published in respected journals and have proven highly reproducible by others.
- The PI’s laboratory has repeatedly brought new technologies from other fields into the lung research arena for the first time, thereby creating many of the essential tools and reagents that have proven enabling for his/her seminal work.
- The PI’s leadership in the broader lung community is evidenced by continued participation in study sessions for peer review as well as organization of national meetings and conferences.
- While reviewers disagreed over the extent to which the PI’s success in the specialized area of lung science would translate to outstanding contributions in stem cell biology per se, many were convinced the PI’s work would have significant impact on the understanding of lung regeneration.
Institutional Commitment and Environment
- Reviewers considered the institutional commitment to be outstanding, as evidenced by extremely positive letters of support as well as matching funds and additional resources for relocation of the PI’s laboratory.
- The applicant organization is a well-regarded research institution with a continued and growing presence in stem cell research and regenerative medicine.
- In addition to providing an excellent research environment, the applicant institution has recruited the PI’s key collaborator, an established lung scientist with complementary expertise in IPF and related areas.
- A motion was made to recommend this application for funding. The motion carried without discussion.