Basic Biology V
$1 133 523
Idiopathic Pulmonary Fibrosis (IPF) is a progressive and generally fatal disease that causes scarring of the lungs and therefore an inability to breathe. Its true prevalence is unknown, as it may go unrecognized for many years, but it is generally thought to affect more than 200,000 people in the USA and is five times more common than cystic fibrosis or amyotrophic lateral sclerosis. The mortality from the disease is very high with about two-thirds of patients dying within five years of diagnosis. The cause and reasons for progression of disease are unknown, but are likely complex and multifactorial, involving genetic predisposition and environmental exposures. A small percentage of cases run in families. Our lack of therapies and understanding of IPF may in large part be due to the fact that there are no good models of the disease. We have developed a disease model of IPF using induced pluripotent stem cell (iPSC) technology, where fibrosis occurs in the dish. This is the first model of human fibrosis in a dish to be described for any fibrotic disease. This model is novel as it is patient derived and patient specific and can be used to better understand the heterogeneity of the disease and to test drugs that individual patients might respond to. Here we plan to increase our understanding of the biology of IPF by altering the microenvironment of the IPF disease model in a dish. This will lead to the development of novel therapeutic strategies for IPF.
Statement of Benefit to California:
Idiopathic pulmonary fibrosis (IPF) is a devastating fatal lung disease that usually occurs in the 7th decade of life. The disease causes scarring of the lungs that make it impossible to breath. The prevalence of IPF is on the rise and expected to double in the next 20 years as the U.S. population continues to age. The prevalence worldwide in the population that is greater than 65 years of age is predicted to be around 125 IPF cases per 100,000 people. California, the most populous state, is also the state with the largest number of people 65 years of age and over (3.6 million people in the year 2000) and therefore the prevalence of IPF in the USA is highest in California with over 5,000 cases. By virtue of the severity of this disease, patients will almost always progress to end stage lung failure and the only therapy available is a lung transplant. In addition to the suffering and disability that IPF causes, the costs associated with caring for patients with IPF, including lung transplant costs, are extremely large. For example a single lung transplant costs roughly $400,000 and this doesn’t include all the follow up care needed post-transplant or any complications. Improving our understanding of and identifying therapies for IPF will therefore have a major impact on patients in California with IPF. Firstly, it will reduce much pain and suffering and secondly it will reduce costs and free up donor lungs, that are in short supply, for other end stage lung disease patients.
Idiopathic pulmonary fibrosis (IPF) is a progressive and generally fatal disease that causes scarring of the lungs leading to difficulty in breathing. IPF has no known cause but involves the development of fibrotic foci and the failure of lung air sacs, the alveoli, to recovery after injury in the lung. In this Track 1, Fundamental Mechanism Award application, the Principal Investigator (PI) proposes to use induced pluripotent stem cell (iPSC) lines derived from somatic cells from familial IPF patients and from healthy controls to study the molecular mechanism(s) of disease pathogenesis. The applicant proposes to investigate: 1) whether IPF results from defects in stromal cells or epithelial cells; 2) the mechanism by which extracellular matrix stiffness affects the iPSC- derived stromal cell phenotype and 3) the signaling pathways involved in fibrosis. Significance and Innovation - The proposed project is potentially highly significant, in that IPF is quite prevalent and effective treatment options are lacking for many patients. - There are no good, representative models for IPF so the use of patient-specific iPSCs that exhibit a disease phenotype may permit investigators to model the disease, understand disease pathogenesis and test novel therapies. - The project is innovative in that the use of iPSC technology to study IPF, and fibrotic disease in general, is novel. Feasibility and Experimental Design - Although the preliminary data show an interesting phenotypic difference between fibroblast cells differentiated from IPF and control iPSCs, a significant concern of the reviewers was whether this phenotype was directly relevant to the disease given the absence of the phenotype in IPF primary fibroblasts from the same tissue. - The project is generally phenomenological and the aims are poorly integrated. The latter two aims in particular were considered exploratory – a “fishing expedition” –that would result in large datasets but would be unlikely to result in a mechanistic understanding of the phenotype - While acknowledging the availability IPF patient-derived iPSC lines from several donors, reviewers noted more patient lines may be required to probe patient heterogeneity given the unknown origins of this complex, heterogeneous disease. - The project, particularly the first aim, offers some opportunity to get at some aspects of the disease mechanism. Principal Investigator (PI) and Research Team - The PI is an expert in lung repair and regeneration and has worked with adult and pluripotent stem cells. S/he is generally well qualified to conduct the proposed research. - Overall, the research team has the appropriate expertise to conduct the research studies. - The research environment is very good. - There was a moderate level of concern expressed by some reviewers that the PI did not have the needed expertise, based on publications, for some of the proposed studies. Responsiveness to the RFA - The project is responsive in that human iPSCs lines from patients and controls have already been derived and a phenotype described for stromal cells derived from iPSC from IPF patients. - The proposal uses hiPSCs derived from patients with familial idiopathic pulmonary fibrosis and healthy controls to study the mechanisms of disease pathogenesis.