Basic Biology IV
$1 387 800
The epithelial lining cells throughout the gas exchanging regions of the lung, termed lung parenchyma, are involved prominently in a number of important human diseases: emphysema, in which epithelial tissue is lost; acute lung injury, where major epithelial injury and tissue remodeling occurs; and pulmonary fibrosis, in which scar tissue effectively replaces the epithelium. In each of these conditions the capacity to generate new alveolar epithelium, and its associated vascular bed, would be of great potential therapeutic value, but such capacity remains beyond the reach of current technology. The rationale for this goal is compelling in no small part because survival following lung transplantation is considerably less than that of other solid organs or bone marrow. The single major objective of this research application is to identify, isolate, and define the functional potential of epithelial stem cells within the human lung parenchyma. The project capitalizes on a collaborative team providing human lungs from normal and diseased subjects and an approach that has successfully identified epithelial stem/progenitor cells in normal and injured mouse lungs. If successful in translating our approach in mice to identifying and analyzing epithelial stem/progenitor cells in the human lung parenchyma, we would have made a clear next step in moving lung stem cell biology toward the clinical arena.
Statement of Benefit to California:
While symptoms of lung disease can be improved, there are currently no therapies that significantly modify the course of several major lung diseases afflicting the population of the State of California, e.g. emphysema and Idiopathic Pulmonary Fibrosis. The goal of this research is to understand the contribution of stem cells in the human lung parenchyma to lung repair and remodeling, with the belief that understanding the role of lung stem cells in repair will lead to ways to modulate their function in a protective manner. If the proposed project is successful this will be a basic but important step forward in modifying intractable lung diseases that afflict Californians.
The epithelial cells located throughout the gas exchanging regions of the lung, the alveolar epithelium, are involved prominently in a number of important human diseases including emphysema, acute lung injury, and pulmonary fibrosis. The potential to regenerate new lung epithelium would be of great therapeutic value, but approaches to achieve this are unknown. The applicant has previously identified a population of epithelial stem or progenitor cells with regenerative potential in the lungs of normal and injured mice. The goal of this proposal is to translate these findings to the human system, to identify a similar cell population in humans and to determine whether such cells could be exploited for repair of injured and diseased lungs. The applicant will employ a variety of approaches to identify, isolate, and functionally characterize human lung epithelial stem cells from normal and fibrotic tissues. Significance and Innovation - The proposal addresses a significant unsolved problem in the field of regenerative medicine. - Although the identification of human lung endogenous stem cells would be a novel finding, reviewers did not consider the approach particularly innovative, since the experimental strategy has already been established and validated in the mouse. - The capacity to generate new alveolar epithelium and its associated vascular bed would be of great potential therapeutic value in the treatment of a number of lung diseases. Feasibility and Experimental Design - Reviewers felt that the applicant had not provided convincing preliminary data to suggest that human lung contains a counterpart to the stem-like cell found in murine lung. Furthermore, there were no data to suggest that, if such a human cell exists, it would express the same types of markers or have the same regenerative potential as the murine cells. This constitutes a significant weakness of the proposal. - There is no compelling evidence to indicate that a culture system for growing and maintaining the human lung stem cells would be feasible. - The experimental plan was weakened by the dependence of Aims 2 and 3 on the success of Aim 1. - Reviewers considered aim 3 to be scientifically interesting but poorly developed. Principle Investigator and Research Team - The PI is an experienced researcher with expertise in lung epithelial and mesenchymal cell biology. - The co-investigators have appropriate expertise in the isolation of cells from human lung tissue. - It is not clear whether there is sufficient expertise on the team to accomplished the proposed experiments that require tissue engineering and organ regeneration. Inclusion of a bioengineer would have strengthened the proposal. Responsiveness - The proposed investigation is responsive to the RFA.