The lung, along with the skin and gut are the three organs in perpetual contact with our environment. The lung has evolved mechanisms for repairing injury due to exogenous noxious agents. The timely repair of lung injury is essential and determines the outcome of life or death. The mechanisms that regulate mature alveolar epithelial stem cell renewal are unknown. Our preliminary studies have led to the hypothesis that interactions between components of the innate immune system expressed by lung alveolar epithelial cells and the cell surface glycosaminoglycan hyaluronan are essential for stem cell renewal and lung repair after injury, and loss of this interaction results in severe lung fibrosis. In this proposal, we will define the mechanisms by which innate immune components, as well as endogenous matrix in lung alveolar epithelial cells promote progenitor cell renewal and lung repair. This is the first link between innate immunity and lung stem cell renewal. Elucidating the mechanisms by which endogenous matrix and innate immune components interact to promote stem cell renewal could lead to novel therapeutic approaches to lung diseases.
Our proposed study is to elucidate the mechanisms by which endogenous matrix and innate immune components interact to promote stem cell renewal which is critical for repair of injured lung. Achievement of the goals of this application will result in a completely novel approach to the treatment of lung diseases. Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which no effective medical therapies exist. Thousands of Californians suffer from pulmonary fibrosis. Lung transplant is the only therapy to prolong life. If the aims of this proposal are achieved, the concepts that drive this field will be changed by demonstrating that fibrotic lung disease can be treated by restoring essential signals necessary for lung stem cell renewal.
This Exploratory Concepts application proposes studies that, if achieved, could result in a novel approach to treat idiopathic pulmonary fibrosis (IPF), a lethal disease that is currently only treatable by transplant surgery. The proposal is based on observations by the Principal Investigator (PI) that key signaling genes that appear to play both a role in lung injury repair and in progenitor cell self-renewal. The overall goal of this application is to define the molecular basis for self-renewal during lung repair. The hypothesis to be tested is that interactions between key innate immune molecules and a cell surface molecule on alveolar stem cells are essential to drive lung repair following injury and that loss of these interactions compromises repair and can lead to lung fibrosis. The PI proposes both in vitro and in vivo studies using a model system to understand the mechanistic basis by which the innate immune and cell surface molecules promote progenitor self-renewal and repair. The PI will also explore the role of the proposed molecules on clonal behavior of human lung progenitor cells from patient samples.
Novelty and Transformative Potential
- This proposal is predicated on the hypothesis that IPF may be treated by promoting signals between components on lung stem cells that stimulate their self-renewal and are necessary for lung repair after injury. This is a highly novel hypothesis with significant transformative potential.
- There are currently no alternative molecular therapies for this lethal disease.
- There is potential applicability for the PI’s paradigm in stem cell self-renewal in other tissues.
Feasibility and Experimental Design
- All the critical reagents including cells and preclinical models appear to be established in the PI’s laboratory. In particular, the lung injury models appear to be standard experimental assays used in the PI’s lab.
-The experimental approach is well-described and will directly test the hypothesis.
- Modest concerns were raised over how well the signaling pathways established in preclinical models will correlate with human lung disease.
Principal Investigator (PI) and Research Team
- The PI is very well established in the field of inflammatory lung disease and has recently begun investigating lung stem cell homeostasis. The PI has recruited strong expertise in lung injury and repair experimental systems. Most importantly, the PI has recruited a top lung stem cell biologist to support these studies.
- The PI has a very strong publication record in top tier journals.
Responsiveness to the RFA
- Overall, the proposal was deemed to be responsive to the RFA.