Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal disease of unknown etiology. The median survival after diagnosis is approximately 3 years, and it is largely refractory to currently available therapies. Improved understanding of the biologic processes involved in development of lung fibrosis, and more complete identification of the molecular mediators driving these processes, are critically needed to develop new effective therapeutic interventions. We have recently identified the potent signaling lipid lysophosphatidic acid (LPA) as a critically important mediator driving the development of bleomycin-induced pulmonary fibrosis in mice. In studies of bronchoalveolar lavage (BAL) fluid from patients, we have generated evidence to suggest that LPA also contributes to the development of IPF in humans. In this application, we propose use Lung Tissue Research Consortium (LTRC) samples from IPF patients and controls to further investigate the role of the LPA pathway in the pathogenesis of human IPF. Specifically, we propose to investigate the hypotheses that: (1) variations in the genes of the LPA receptors and/or the enzymes involved in LPA metabolism are associated with the development of IPF;and (2) mRNA expression levels of these receptors and/or enzymes are upregulated in the lungs of IPF patients.
In Aim 1 of this application, we will evaluate our first hypothesis by comparing the genotypes of IPF patients and controls at known single nucleotide polymorphisms (SNPs) in the genes of the LPA receptors and the enzymes involved in LPA metabolism.
In Aim 2, we will evaluate our second hypothesis by comparing the levels of mRNA expression of these genes in the lungs of IPF patients and controls. Finding associations between the development of IPF and variations in the genes of the LPA pathway, and/or the expression profile of these genes in the lung, would provide further evidence that this pathway plays a causal role in IPF, and support our ultimate hypothesis that targeting the LPA pathway will lead to novel and effective therapies for this devastating disease. (End of Abstract)
Project Narrative: Idiopathic Pulmonary Fibrosis (IPF) is associated with unacceptably high morbidity and mortality. Improved understanding of the biologic processes involved in development of lung fibrosis, and more complete identification of the molecular mediators driving these processes, are critically needed to develop new therapies for this disease. The proposed studies seek to demonstrate that the potent lipid mediator lysophosphatidic acid (LPA) importantly contributes to the development of IPF, to provide evidence that targeting this mediator may represent an effective new therapeutic strategy for this devastating disease.
