Funding opportunities

Modulation of Stem Cell PTHrP/Wnt Signaling to Prevent Chronic Lung Disease

Funding Type: 
SEED Grant
Grant Number: 
RS1-00472
Funds requested: 
$500 000
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Chronic lung disease is rapidly becoming the primary cause of death in the USA. It is particularly an emerging health problem in Southern and Central California, and recent research indicates a significant loss of lung function in children between the ages of 10 and 18 within these regions. Environmental pollutants, including automobile emissions and agricultural chemicals are the main causal agents for chronic lung diseases. Constant exposure to ever-increasing air pollution in California is of great concern since loss of lung function in children projects to chronic lung disease in adults. The most pronounced effects of pollution-related lung deficits occur later in life. Reduced lung function is a strong risk factor for complications and death during adulthood. The onset of lung disease can be traced all the way back to infancy, and even to the fetal period. For example, exposure to tobacco smoke during fetal life can permanently alter the lung’s development, making it greatly vulnerable to later chronic lung disease, including predisposition to asthma. Currently, there is no intervention that can arrest or cure evolving or established chronic lung disease. This is due to a lack of our understanding of the molecular processes involved in both normal and abnormal lung development; in particular, how insults that lead to chronic lung disease affect normal lung development, and why the body’s normal repair mechanisms fail to overcome these insults. Knowledge of the intrinsic molecular mechanisms that allow for resistance to inflammation and recruitment of stem cells for repair would allow engineering of such cells for treatment. Our laboratory, comprising basic, clinical, and translational scientists, is focused on unraveling the mechanisms of both normal and abnormal lung development. Our recent work has led to the discovery of a novel, fundamental mechanism for the onset, development and exacerbation of virtually all forms of chronic lung diseases in both children and adults. We have found that when exposed to insults that lead to chronic lung diseases, critically vital “fat-containing” (good) cells in the normal lung transform into “muscle-like” (bad) cells that are the hallmarks of a chronically damaged lung, making the subjects more prone to asthma. Importantly, we have observed that exogenously administered agents that help in maintaining the “fat cell” characteristics of the relevant lung cells can effectively prevent lung damage due to injurious agents. The proposed studies aim to obtain new insights into how stem cells from within the body could be driven to “fat-containing” good cells that are critical for normal lung development and repair of injured lung. If successful, such engineered stem cells will have tremendous commercial as well as clinical potential for treating or reversing virtually all forms of chronic lung disease, and offer an opportunity to cure these diseases effectively in both newborns and adults for the first time.
Statement of Benefit to California: 
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States, killing more than 112,000 people each year, according to the American Lung Association. As many as 24 million Americans have some impairment of lung function, with an estimated 11.4 million adults age 18 or over, reportedly suffer from established COPD. In 2004, the annual cost to the nation from respiratory diseases was 37.2 billion dollars that included 21 billion in direct health care cost, 7.5 billion in indirect morbidity cost, and 8.7 billion in indirect mortality cost. Despite these staggering statistics, COPD is the most under-funded of all the diseases in the USA, with a mere $508 spent on research per COPD death. Pulmonary diseases are a particular problem in Southern and Central California, due largely to ever increasing air pollution. There is currently no intervention that can arrest or cure evolving or established chronic lung disease. Knowledge of the intrinsic molecular mechanisms that allow for resistance to inflammation and recruitment of stem cells for repair, sought here, would allow engineering of such cells for treatment. Our research group is among the select few in the nation focused on unraveling the mechanisms of both normal and abnormal lung development. Our recent work on rodent model has led to the discovery of a novel fundamental mechanism for the onset, development and exacerbation of virtually all forms of chronic lung diseases in both children and adults. We have found that when exposed to insults that lead to chronic lung diseases, critically vital lipid-laden lipofibroblasts present in the alveolar wall of the healthy lung transdifferentiate into myofibroblasts that characterize chronically damaged lung. Importantly, we have discovered that exogenously administered agents that help in maintaining the lipofibroblastic characteristics of the relevant lung cells can effectively prevent lung damage due to agents that are injurious for the lung. We believe that our proposed studies with hESCs will provide within 3-5 years new insights into how stem cells from within the human body could be driven to a lipofibroblastic phenotype that is critical to normal lung development and repair. Research funding support from CIRM will not only permit validation of the proof-of-the principle for bidirectional lipofibroblast-myoblast transdifferentiation in human cells but will also accelerate the discovery process with tremendous translational potential to treat or reverse virtually all forms of chronic lung disease. Our proposed investigations promise a unique opportunity to cure chronic lung diseases effectively in both newborns and adults for the first time. Intellectual capital arising from this proposal is likely to be rapidly translated into therapeutic drugs to avert and cure chronic lung diseases for millions of Californians, who would otherwise be at continued risk for developing these conditions in adulthood.
Review Summary: 
SYNOPSIS: This application focuses on understanding the signals that promote the differentiation of lung epithelial and alveolar progenitor cells following lung injury. In Aim 1 the applicants will explore the potentially antagonistic relationship between parathyroid hormone related protein (PTHrP) and Wnt signaling on the differentiation of mesenchymal progenitor cells into lipo- versus myo- fibroblasts. In Aim 2 the applicant will expose embryoid bodies to conditioned medium from mesenchymal cells treated with PTHrP to determine if these cells are producing secreted proteins that stimulate alveolar cell differentiation. INNOVATION AND SIGNIFICANCE: PTHrP is known to be essential for normal lung development and recent evidence suggests that it may also play a role in the response of the lung to injury. This proposal represents an attempt to develop a model system for studying the effect of this protein on the progenitor cells involved in lung development and healing following injury. The problem of lung fibrosis and chronic lung disease is serious and significant. The ability to control the LIF fate, and perhaps generate relevant progenitors in vitro would be important. STRENGTHS: The applicants have extensive experience in studying lung development and healing following injury, and have contributed to our knowledge of the roles that PTHrP play in these processes. The applicants also bring an important clinical perspective to this interesting biological problem. Because of their background, the PI and co-PI bring expertise in the field of lung cell physiology to the hESC system. Aim 1 is fairly straightforward, assuming appropriate mesenychmal progenitor cells (MPCs) are derived, and could confirm the suspected pathways as relevant. The ability to define factors in conditioned medium (CM), beyond testing for leptin, is less clear. WEAKNESSES: This is a confusing application that is poorly written, ill-conceived and overly-ambitious. Confidence in the proposal is not inspired by statements that seem to attribute all chronic lung disease to uninhibited Wnt signaling. In Aim 1 the applicants will study the effect of PTHrP on mesenchymal cells that have been derived from hESCs in vitro. At no point do the applicants explain the relationship between these primitive cells and the real target cells of PTHrP in vivo, which are alveolar lipofibroblasts. One reviewer pointed out that there is no prior evidence that PTHrP is involved in the conversion of very primitive mesenchymal progenitor cells into alveolar fibroblasts. In this Aim the applicants also vaguely propose to do a host of overexpression and knockdown experiments on components of the PTHrP and Wnt pathways, as well as gene and protein expression studies and metabolomics. The point of all this is entirely unclear, and the work involved would be impossible to handle for the single postdoctoral fellow who will be doing all the experiments. Aim 2 involves conditioned medium experiments in a very technically demanding protocol. How this will be pursued beyond the descriptive stage is also entirely unclear. TAnother reviewer thought that the major issue is whether the PI can derive relevant and bipotential MPCs from cultured hESCs. The cultures are likely to be heterogeneous and without a clean and defined progenitor population the project can not proceed. While the PI was funded by an NIH supplement it is not clear what progress was achieved. While the project seeks to translate current data from rat models to the hESC system, it is less clear how much new information will be gained, short of proving that the same pathways do or do not function in hESC cultures. How will this lead to novel therapies? Could not these pathways be tested for relevance currently in animal models? It will be important to demonstrate the derivation of bipotential MPCs (capable of lipo or myofibroblast phenotype) before the project can be evaluated for feasibility. DISCUSSION: There was no further discussion following the reviewers' comments.
Conflicts: 

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