Large Noncoding RNAs as Therapeutic Targets in IPF
Abstract
Pulmonary fibrosis describes a condition in which the normal lung anatomy is replaced by a process of active lung scarring. The cause of the condition can be unknown as in idiopathic pulmonary fibrosis (IPF) or secondary to familial disorders, lung involvement in autoimmune diseases, or exposure to environmental toxins, chemical warfare, drugs, foreign antigens, or radiation. IPF, the most common of these disorders, is a fatal disease and nearly half of the afflicted individuals do not survive beyond 5 years. The disease affects close to 120,000 persons in the United States, and so far is incurable. A common feature to all forms of pulmonary fibrosis is abundance of fibroblasts, cells that form the support of lung and accumulation of myofibroblasts, fibroblast-like cells that exhibit some smooth muscle characteristics and secrete extracellular matrix, the major component of the scar in the lung. We recently discovered that the lungs of patients with IPF exhibit a distinct repertoire of a family of RNA molecules called large intergenic non-coding RNAs (LincRNA). Unlike other RNA molecules, these molecules do not code for proteins; instead, they act as regulators of the ability of other genes to be expressed. The most decreased lincRNA in IPF lungs is called FENDRR, a lincRNA that is important in normal lung development but so far unstudied in the adult lung. We determined that the decreases in FENDRR in IPF lungs are specific to IPF. Experiments we performed suggested that when FENDRR is decreased, fibroblasts become more like myofibroblasts, the cells underlying the lung pathology in IPF. In this application, we aim to test the novel hypothesis that FENDRR maintains fibroblasts differentiation status through its effects on the expression of genes, organization; therefore, when FENDRR expression is decreased, fibrosis is facilitated through persistence of myofibroblasts. The experiments we will perform will determine the mechanisms by which FENDRR is active in fibroblast cells, determine whether inhibition of FENDRR causes fibrosis and more importantly whether administration of FENDRR may cure or improve fibrosis in mice, and assess the role of FENDRR in the human lung. The successful completion of our experiments will substantially impact our understanding of pulmonary fibrosis and more importantly will allow us to determine whether FENDRR should be further evaluated as a therapeutic intervention in pulmonary fibrosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610646
Entities
People
- Naftali Kaminski
Organizations
- United States Army
- Yale University