Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing lung disease for which there is no cure. IPF is associated with aging and will likely become more common as our population ages. The pathophysiology of IPF remains incompletely understood, but the alveolar epithelium, specifically the senescent alveolar epithelium, has recently been implicated in this disease. Telomeres are DNA and protein caps on the ends of chromosomes. Short telomeres are a known risk factor for IPF, and mutations in telomere maintenance genes cause IPF. In the setting of telomere dysfunction, alveolar epithelial cells (AECs) rather than dying, preferentially become senescent. Senescent AECs have been shown to secrete pro-survival and pro-fibrotic proteins. This is known as the senescence-associated secretory phenotype (SASP). Multiple SASP proteins have been shown to be capable of inducing their own secretion through autocrine (feed-forward) pathways and to also signal in the traditional paracrine fashion to bystander, non-senescent cells. CXCL12, a SASP protein, has previously been shown to be capable of both autocrine and paracrine signaling in an AEC-like cell line, but the downstream transcriptional and proteomic consequences have not been fully explored. CXCL12 has also been shown to play an important role in lung morphogenesis, but the major cell-type of origin of CXCL12 is not known. The main objective of this proposal is to determine the role of CXCL12 as an autocrine and paracrine mediator originating from a senescent alveolar epithelium and whether loss of CXCL12 signaling from the pulmonary epithelium prevents the fibrotic response. The downstream signals CXCL12 generates on the alveolar epithelium itself will be explored in depth.
Aim 1 will utilize a novel conditionally senescent alveolar epithelial-like cell line to explore the consequences of autocrine and paracrine CXCL12 signaling onto the epithelium itself.
Aim 2 will seek to determine the function of pulmonary epithelium-derived CXCL12 in a mouse model of pulmonary fibrosis. The knowledge gained from the completion of these studies may promote further research into the role of the alveolar epithelium in IPF and influence the allocation of resources toward the development of CXCL12 pathway-based therapeutics for this disease. Furthermore, this project will provide the applicant the opportunity to develop expertise in lung epithelial cell biology and immunology. The training plan will promote acquisition of advanced laboratory skills including flow cytometry, CRISPR/Cas genome editing, proteomics, and multiple elements of animal modeling. Additionally, didactic courses have been selected to supplement the hands-on training received and promote the advancement of the applicant?s career. Combined with close mentoring and the robust research environment at the University of Pittsburgh, this proposal will support the candidate?s development as an independent physician-scientist.
Idiopathic pulmonary fibrosis (IPF) is a disease of aging whose prognosis is often worse than many cancers. Alveolar epithelial cell senescence is believed to play a role in the pathogenesis of IPF, but the mechanistic connections have not been established. The goal of this project is to improve the understanding of the function of epithelial-derived CXCL12 in the development of IPF, which could lead to new treatments for this disease.
