Cell Type-Specific KLF4 Regulation of Lung Fibrosis
Abstract
Our proposal investigates a specific Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Area of Encouragement: “research into the pathobiology and molecular mechanisms underlying the development of pulmonary fibrosis.” Idiopathic pulmonary fibrosis, known as IPF, is a chronic and progressive form of pneumonia that has no known cause and is highly lethal. Indeed, IPF has a dismal survival of, on average, only 2-3 years after initial diagnosis and is the cause of 40,000 deaths annually in the United States of America alone. Undoubtedly, improved therapies are desperately needed for this disease. A key reason for the lethality of pulmonary fibrosis and the sub-optimal treatments is that our understanding of the biological processes underlying this disease are poorly understood. Our studies aim to improve our understanding of the processes that go awry in pulmonary fibrosis and thus, suggest novel therapeutic strategies to combat this devastating disease. To this end, we have assembled a synergistic team with diverse expertise that have come together with the collective goal of making seminal insights into pulmonary fibrosis. The Initiating Principal Investigator (PI) (Daniel Greif, MD; Associate Professor of Medicine and Genetics, Yale University) has expertise in advanced mouse genetic, mouse models of lung disease and the role of Kruppel-like factor 4 (KLF4; a molecule that is central to the proposed studies) in lung disease. The Partnering PI (Erica Herzog, MD, PhD; Associate Professor of Medicine, Yale University) is an expert in human pulmonary fibrosis as well as mouse models of this disease. The co-Investigator (Rob Homer, MD, PhD; Professor of Pathology and Medicine, VA Connecticut Healthcare System and Yale University) is a leading non-cancer human lung pathologist and has vast experience in the pathology of lung fibrosis in humans and experimental models, including the mouse. Biological structures are composed of two compartments: the cellular compartment and the extracellular compartment. The extracellular compartment is largely comprised of connective tissue. In lung fibrosis, this extracellular component accumulates excessive amounts of aberrantly stiff connective tissue that markedly impairs the function of the lung, which requires elasticity for each inhalation and exhalation. A specialized cell type in the lung, known as myofibroblasts, have been implicated as the source of most of the excessive extracellular connective tissue in lung fibrosis. The origin of these myofibroblasts and the mechanisms underlying their generation of fibrotic tissue are incompletely understood. Our preliminary studies indicate that reducing the amount of KLF4 in specific cell types in the lung have dramatic effects on the accumulation of myofibroblasts and fibrosis. Interestingly, deleting the gene encoding KLF4 in one cell type markedly reduces the accumulation of myofibroblasts and connective tissue in a model of lung fibrosis, and we have begun to delineate the molecular mechanisms underlying these changes. Surprisingly, however, deletion of Klf4 in a distinct cell type has the opposite effect: excessive lung myofibroblasts and fibrotic tissue. The main goal of the proposed studies is to understand why the effects of KLF4 in these different cell types have such dramatically different effects on the course of lung fibrosis. To this end, we use tissue samples from patients with IPF, two mouse models of pulmonary fibrosis and cells isolated from these humans and mice. We aim to discover underlying molecular pathways that account for cell type-specific effects of KLF4 and thereby, uncover molecules that could potentially be specifically targeted in novel treatments to attenuate the markedly negative impact that lung fibrosis has on human health.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810629
Entities
People
- Daniel M. Greif
Organizations
- United States Army
- Yale University